Experimental Brain Research

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Electromyography (EMG) recordings in the spontaneous (SPON) breathing condition from a representative participant. The perturbation onset (dashed line), EMG burst onset (arrow), and where the average rectified value (ARV) amplitude is calculated (shaded area under curve) are shown. EMG data are averages of 24 perturbations. MH Medial hamstring, QUADS Quadriceps, TA Tibialis anterior, SOL Soleus, GASTROCS Gastrocnemii
Muscle latency post perturbation in spontaneous (SPON; gray) and SLOW (white) breathing conditions. Data represent group mean and standard deviation bars with lines connecting individual participant’s values between conditions in each muscle group. EMG Electromyography, QUADS Quadriceps, MH Medial Hamstring, GASTROC Gastrocnemii, SOL Soleus, TA Tibialis anterior
Normalized electromyography (EMG) amplitude for 200 ms from the onset of muscle activation following a postural perturbation in spontaneous (SPON; gray) and SLOW (white) breathing conditions. Data shown are group mean and standard deviation bars with lines connecting individual participant’s values between conditions in each muscle group. QUADS Quadriceps, MH Medial Hamstring, GASTROC Gastrocnemii, SOL Soleus, TA Tibialis anterior
Maintaining standing balance is vital to completing activities in daily living. Recent findings suggest an interaction between cardiovascular and postural control systems. Volitional slow breathing can modulate the cardiovascular response and affect postural control during quiet standing. However, the effects of slow breathing during threats to standing balance have not been studied. The study examined the effect of slow breathing on the latency and amplitude of postural muscle responses to perturbations of the base of support in healthy, young adults. Twenty-seven participants completed two balance perturbation tasks in standing on an instrumented split-belt treadmill while breathing spontaneously and breathing at 6 breaths per minute. Each perturbation task consisted of 25 posteriorly directed translations of the treadmill belts every 8–12 s. Muscle latency and muscle burst amplitude were measured using surface electromyography from the right limb for the quadriceps (QUADS), medial hamstring (MH), gastrocnemii (GASTROC), soleus (SOL), and tibialis anterior (TA) muscle groups, while a respiratory belt was used to record respiratory rate. Results indicated that during the slow breathing task both muscle latency (p = 0.022) and muscle burst amplitude (p = 0.011) decreased compared to spontaneous breathing. The EMG pre-perturbation activation was not significantly different in any muscle group between conditions (p > 0.167). The study found that reducing respiratory rate to approximately 6 breaths per minute affects the neuromuscular responses in the lower limb muscles to perturbations.
The position of the MUSE electrodes on scalp. AF7, AF8, TP9 and TP10 are channel electrodes and FPZ is marked as the reference electrode in this device. In this study, the data is pooled from AF7 and AF8 for analysis
The oddball paradigm test: Each block of trials included 75% of the standard stimulus (purple) for 75% and 25% of the oddball stimulus (orange). The stimuli were presented at random intervals at each block after the fixation cross. Each stimulus lasted for 800–1200 ms at the center of the dark gray screen
The individual ERP waveforms for Standard and Oddball conditions in migraine
The individual ERP waveforms for Standard and Oddball conditions in migraine
Comparison of the Grand Difference waveforms in migraine and control groups
New findings from migraine studies have indicated that this common headache disorder is associated with anomalies in attentional processing. In tandem with the previous explorations, this study will provide evidence to show that visual attention is impacted by migraine headache disorders. 43 individuals were initially recruited in the migraine group and 33 people with non-migraine headache disorders were in the control group. The event-related potentials (ERP) of the participants were calculated using data from a visual oddball paradigm task. By analyzing the N200 and P300 ERP components, migraineurs, as compared to controls, had an exaggerated oddball response showing increased amplitude in N200 and P300 difference scores for the oddball vs. standard, while the latencies of the two components remained the same in the migraine and control groups. We then looked at two classifications of migraine with and without aura compared to non-migraine controls. One-Way ANOVA analysis of the two migraine groups and the non-migraine control group showed that the different level of N200 and P300 amplitude mean scores was greater between migraineurs without aura and the control group while these components’ latency remained the same relatively in the three groups. Our results give more neurophysiological support that people with migraine headaches have altered processing of visual attention.
Panel A shows an illustration of the instrumented object with force sensors for recording digit forces. A motion capture system tracked the positions of four reflective markers fixed to the object. Panel B shows the experimental setup. Participant sat in front of a computer screen, grasped the object in a pinch grasp, and tracked visual targets by moving the object. Panel C shows the visual feedback. Target represented by a square, and object position represented by ‘X’-shaped cursor. Target stayed in one position for the steady task, and it jumped up or down for the choice reaction time (CRT) task. The target and cursor moved vertically for both vertical and horizontal object movements. The number of upward and downward jumps of the target were equal and randomized within each task block
Representative time series for the pressing forces of the thumb (black solid line) and index finger (dashed red line) for the steady task in panel (A) and for the choice reaction time task in panel (B). The data in the shaded analysis window was used for analysis. The normal forces of the thumb and the index finger show a small mismatch because the sensor cables exert a small force on the object. This difference does not influence our key results because it is small, it is consistent across all conditions, and it is irrelevant for the temporal structure between the two force time series
Panel A shows a representative cross recurrence plot for the thumb and index finger pressing forces. Panel B shows the normalized time series of the two forces that are used to obtain the cross recurrence plot in A
Panel A shows the mean grip force during the analysis window with individual data points for each trial for all participants. Panel B shows the slopes of the best fit line to the grip-force–time data within the analysis window with individual data points for each trial for all participants. Negative slope indicates slacking in grip force (see text). ‘*’ indicates significant differences (p < 0.05)
Trapping time obtained from the cross recurrence plots for the thumb and the index finger pressing forces with individual data points for each trial for all participants. Higher value indicates weaker coupling between the forces. ‘*’ indicates significant differences (p < 0.05)
Humans closely coordinate the grip force exerted on a hand-held object with changes in the load arising from the object’s dynamics. Recent work suggests the grip force is responsive to the predictability of the load forces as well. The well-known grip-force–load-force coupling is intermittent when the load arising from volitional movements fluctuates predictably, whereas grip force increases when loads are unpredictable. Here, we studied the influence of expected but uncertain volitional movements on the digit forces during a static grasp. Young, healthy participants used a pinch grasp to hold an instrumented object and track visual targets by moving the object. We quantified the mean grip force, the temporal decline in grip force (slacking), and the coupling between the pressing digit forces that yield the grip force during static prehension with no expectation of movement, and during the static phase of a choice reaction time task, when the participant expected to move the object after a variable duration. Simply expecting to move the object led to sustained (for at least 5 s) higher magnitude and lower slacking in the grip force, and weaker coupling between the pressing digit forces. These effects were modulated by the direction of the expected movement and the object’s mass. The changes helped to maintain the safety margin for the current grasp and likely facilitated the transition from static to dynamic object manipulation. Influence of expected actions on the current grasp may have implications for manual dexterity and its well-known loss with age.
Number of ball rotations in the fast and slow groups. The horizontal axis indicates the number of ball rotations. The error bar indicates the standard deviation
Grand averaged waveforms of all participants in the BR task (solid line) and stationary task (dotted line) at each electrode site. Vertical dotted lines indicate stimulus onset
SEP amplitudes of the two groups in the BR task and the stationary task at each electrode site. The vertical axis indicates SEP amplitude. Error bar indicates standard deviations. Asterisks indicate significant differences (p < 0.05) between the tasks and daggers indicate significant interactions (p < 0.05) of TASK × GROUP
Plot of the BR number relative to ΔSEP for all participants. The vertical axis indicates ΔP45. Values more and less than 0 indicate suppressed and increased SEP amplitude in the BR task compared to the stationary task, respectively. The horizontal axis indicates the number of ball rotations
During voluntary muscle contraction, sensory information induced by electrostimulation of the nerves supplying the contracting muscle is inhibited and the amplitude of the corresponding somatosensory evoked potential (SEP) decreases. This phenomenon is called “gating.” The reduction of the SEP amplitude is reportedly significantly larger when task performance is high. However, the relationship between dexterous movement skills and gating remains unclear. In this study, we investigated through a ball rotation (BR) task how dexterous movement skills affect the SEP amplitudes. Thirty healthy subjects performed the BR task comprising the rotation of two wooden balls as quickly as possible. We estimated the median number of ball rotations for each participant and classified the participants into two (fast and slow) groups based on the results. Moreover, we recorded SEPs, while the subjects performed BR tasks or rested. SEP amplitude reduction (P45) was significantly larger in the fast than in the slow group. We also observed that the P45 amplitude during the BR task was attenuated even more so in the case of the participants with better dexterous movement skills. Our results suggest that the participants with better dexterous movement skills might display stronger somatosensory information suppression because of increasing the motor cortex activity and the afferent input during the BR task.
At present, one of the main therapeutic challenges comprises the development of technologies to improve the life quality of people suffering from different types of body paralysis, through the reestablishment of sensory and motor functions. In this regard, brain–machine interfaces (BMI) offer hope to effectively mitigate body paralysis through the control of paralyzed body parts by brain activity. Invasive BMI use chronic multielectrode implants to record neural activity directly from the brain tissue. While such invasive devices provide the highest amount of usable neural activity for BMI control, they also involve direct damage to the nervous tissue. In the cerebral cortex, high levels of the enzyme NADPH diaphorase (NADPH-d) characterize a particular class of interneurons that regulates neuronal excitability and blood supply. To gain insight into the biocompatibility of invasive BMI, we assessed the impact of chronic implanted tungsten multielectrode bundles on the distribution and morphology of NADPH-d-reactive neurons in the rat frontal cortex. NADPH-d neuronal labeling was correlated with glial response markers and with indices of healthy neuronal activity measured by electrophysiological recordings performed up to 3 months after multielectrode implantation. Chronic electrode arrays caused a small and quite localized structural disturbance on the implanted site, with neuronal loss and glial activation circumscribed to the site of implant. Electrodes remained viable during the entire period of implantation. Moreover, neither the distribution nor the morphology of NADPH-d neurons was altered. Overall, our findings provide additional evidence that tungsten multielectrodes can be employed as a viable element for long-lasting therapeutic BMI applications.
Electrical stimulation of the right median nerve can aid coma arousal after traumatic brain injury (TBI). This study aimed to confirm the efficacy further and explore possible mechanisms of right median nerve electrical stimulation (RMNS). Five comatose patients after severe TBI from May to September 2020 in the Tianjin Medical University General Hospital received RMNS for 2 weeks besides standard management. After the 2-week treatment, the mean Glasgow Coma Scale (GCS) and neurophysiological examination were used. We then investigated the alterations in microRNA (miRNA) expression in cerebrospinal fluid (CSF) by high-throughput whole transcriptome sequencing, analyzed the data by Gene Ontology (GO) and pathway analysis, and constructed the miRNA–target gene network. Patient awareness and brain function showed a more rapid increase after treatment. We also found 38 differently expressed miRNAs, 34 of which were upregulated and 4 downregulated. GO analysis showed a relation of these differentially expressed miRNAs with neuronal growth, repair, and neural signal transmission. The most highly correlated pathways were primarily associated with the tumor necrosis factor (TNF) signaling pathway and dopaminergic synapse. The application of RMNS effectively promoted early awakening in comatose patients with severe TBI. Moreover, differentially expressed miRNAs might reduce neuronal apoptosis and increase dopamine levels by regulating target gene expression, thus participating in the specific biological process after arousal therapy. Our study provided novel targets for further research on the molecular mechanisms of RMNS arousal treatment and a new way to treat neurotraumatic diseases.
Reaching movements of the arms are accompanied by anticipatory (APM) and compensatory postural motion (CPM) that counteract the resulting perturbations to body stability. Recent research has shown that these postural actions are also observable in the context of imagined arm movements. As motor imagery (MI) shares many neurophysiological and behavioral characteristics with physical movements, and MI training can affect subsequent performance, MI tasks provide a good setting for studying the anticipatory aspects of postural control. This study investigated APMs and CPMs of the head and hip of healthy young and older adults in the temporal vicinity of physical and imagined forward raises of the dominant and non-dominant arm. When MI of the dominant arm was self-initiated, both age groups showed APM in the anteroposterior plane. When the self-initiated MI was of the non-dominant arm, only the older group showed anteroposterior APM. The older group did not show APM when an expected arm movement (or MI) was made to an external signal. This suggests an age-related deficit in coordinating postural preparation with external events. Only the older group showed mediolateral APM, and only for dominant arm MI, indicating sensitivity to potential perturbation to the weaker, non-dominant side of the body. Overall, the older group showed more anticipatory postural motion at the head. Systematic APM for manual MI suggests that MI training may be an effective intervention for anticipatory postural control. An integrated model of postural support for executed and imagined limb movements is suggested.
Performances of connectome-based predictive models (CPMs) adjusted for mean FD by leave-one-out cross-validation. Correlation between the chronological and predicted age via (a) a positive network, (b) a negative network, and (c) a combined network model, wherein both the positive and negative network strengths were applied
Functional connections and macroscale brain regions predicting chronological age obtained from positive and negative models. All edges occurred in iteration (1000 times) of CPM construction. The connections selected by CPM are plotted as the edges within 10 macroscale regions. The top five highest degrees are plotted as the bold line. Each degree of the edge is proportional to a sphere of size determined by the glass brain mapping. a The 596 edges in the positive network are visualized in red. b The 1102 edges in the negative network are visualized in blue
The colored matrices plotted as the number of edges within and between each macroscale region and predefined network. a Inter- and intraparietal connection had the highest number of edges for predicting chronological age in the positive network of the macroscale brain regions. The negative network had the highest inter- and intralimbic connection of the macroscale brain regions. b In the predefined canonical functional networks, the positive network had the highest degree within the subcortical–cerebellum network, and the subcortical–cerebellum network showed many significant edges with other networks for age prediction. The negative network showed the highest degree within the subcortical–cerebellum network and between the subcortical–cerebellum and motor networks
The functional connections for predicting the chronological age obtained from a tenfold cross-validation as an internal validation. All edges occurred in every iteration of the CPM construction. a The connectivity patterns were distributed in the macroscale brain regions. The nodes that had the top five highest degrees are plotted as the bold line. The 238 edges in the positive network are plotted in red, and the 470 edges in the negative network are plotted in blue. b Each network is represented by a colored matrix that shows the connection within and between the macroscale brain regions. c Functional connections within and between each pair of functional networks
Results of external validation for CPM with independent test datasets. Correlation between the chronological and predicted age using (a) a positive network, (b) a negative network, and (c) a combined network model constructed from the training set
Changes in the brain with age can provide useful information regarding an individual’s chronological age. studies have suggested that functional connectomes identified via resting-state functional magnetic resonance imaging (fMRI) could be a powerful feature for predicting an individual’s age. We applied connectome-based predictive modeling (CPM) to investigate individual chronological age predictions via resting-state fMRI using open-source datasets. The significant feature for age prediction was confirmed in 168 subjects from the Southwest University Adult Lifespan Dataset. The higher contributing nodes for age production included a positive connection from the left inferior parietal sulcus and a negative connection from the right middle temporal sulcus. On the network scale, the subcortical–cerebellum network was the dominant network for age prediction. The generalizability of CPM, which was constructed using the identified features, was verified by applying this model to independent datasets that were randomly selected from the Autism Brain Imaging Data Exchange I and the Open Access Series of Imaging Studies 3. CPM via resting-state fMRI is a potential robust predictor for determining an individual’s chronological age from changes in the brain.
Brain slice culture (BSC) is a well-known three-dimensional model of the brain. In this study, we use organotypic slices for studying neuro-lymphatic physiology, to directly test the longstanding assumption that the brain is not a hospitable milieu for typical lymphatic vessels. An additional objective is to model fluid egress through brain perivascular space systems and to visualize potential cellular interactions among cells in the leptomeninges including alterations of cellular geometry and number of processes. Immortalized lymphatic rat cell lines were used to seed organotypic brain slices. The brain slice model was characterized by monitoring morphologies, growth rates, degree of apoptosis, and transport properties of brain slices with or without a lymphatic component. The model was then challenged with fibroblast co-cultures, as a control cell that is not normally found in the brain. Immortalized lymphatic cells penetrated the brain slices within 2–4 days. Typical cell morphology is spindly with bipolar and tripolar forms well represented. Significantly more indigo carmine marker passed through lymphatic seeded BSCs compared to arachnoid BSCs. Significantly more indigo carmine passed through brain slices co-cultured with fibroblast compared to lymphatic and arachnoid BSCs alone. We have developed an organotypic model in which lymphatic cells are able to interact with parenchymal cells in the cerebrum. Their presence appears to alter the small molecule transport ability of whole-brain slices. Lymphatic cells decreased dye transport in BSCs, possibly by altering the perivascular space. Given their direct contact with the CSF, they may affect convectional and diffusional processes. Our model shows that a decrease in lymphatic cell growth may reduce the brain slice’s transport capabilities.
Trial sequence (not to scale). After clicking on a central dot (which centred the cursor position for each trial), participants saw a group of bugs consisting of three colours. In this figure, the participant must click on “invasive” blue or pink bugs, but avoid the “protected” orange bugs. In No Change trials, the invasive bug did not change colour. In Irrelevant Change trials, the first invasive bug that the participant moved their cursor towards changed to the other invasive colour (in this example, from blue to pink). In Incorrect Change trials, this bug changed to the protected colour (in this example, from blue to orange), inducing a mistake when participants were not able to prevent clicking on the bug quickly enough. Upon mouse click, the screen remained static for a delay of 200, 500, or 800 ms, following which the clicked bug was shown as being broken into pieces, along with a 100 ms auditory tone. Finally, participants estimated the time between their click and the outcome by clicking anywhere on the interval estimate scale
Mean interval estimates separated by Trial Type (collapsed across the three action–outcome delays). The main effect of Trial Type was qualified by significantly shorter mean interval estimates in Incorrect Change trials relative to the other trials. Error bars denote SEM. ***p < .001; n.s. not significant (p > .05)
Exploratory analysis of mean interval estimates separated by Trial Type and Action–Outcome Delay. At 200 ms delays, there was no main effect of Trial Type. At 500 ms and 800 ms delays, interval estimates were significantly shorter on Incorrect Change trials relative to the other trial types. Error bars denote SEM. ***p < .001; n.s. not significant (p > .05)
Temporal binding is an illusion in which the temporal interval between two events appears compressed. In the context of intentional actions, this effect is observed as a compression of the perceived interval between these actions and their causal outcomes. This ‘intentional binding effect’ has been used to investigate the Sense of Agency, which is the experience of intentionally causing an outcome through volitional action. Intentional binding is reduced for negative outcomes such as error feedback, but the role of mistakes (e.g., errors of commission) for binding and agency has not been extensively studied. In our study, participants played a virtual game in which they attempted to ‘splat’ (hit) visual stimuli that looked like coloured bugs, using mouse clicks. On some trials, stimulus colours changed unpredictably immediately before actions were made, sometimes inducing mistakes. Actions were thus clearly identifiable as mistakes at the time of their onset before any outcome feedback had been provided. Participants reported shorter action–outcome intervals when stimuli changed, but only when this change caused a mistake according to the game’s rules. This suggests that intentional binding is strengthened by errors of commission. We discuss how this effect may be accounted for by agency itself and via more general processes such as changes in arousal.
Force scaling for three weights (light, medium and heavy) in the no-change conditions for the first peak of grip force rate (peakGFR1) and first peak of load force rate (peakLFR1), for Experiment 1 (a) and Experiment 2 (b). Markers indicate the three modality conditions (vision, haptic and visuohaptic) with standard errors. Thin lines represent individual participants. Note that a main effect of weight was found for all parameters in both experiments
Differences between change and no-change conditions for Experiment 1 (a) and Experiment 2 (b) in the three modality conditions (vision, haptic and visuohaptic), for the first peak of grip force rate (peakGFR1) and first peak of load force rate (peakLFR1). Light and dark green symbols represent light and heavy objects, respectively. The lifted object is plotted by comparing the first cue when it was small (light, x-axis) or large (heavy, y-axis). If the object is lifted similarly, irrespective of the first cue, values will fall on the diagonal black line. If the value is different from the black line, there is either incomplete correction (force is scaled towards the first cue and less to the object weight) or overcompensation (force is scaled towards the object weight, but more than in the no-change condition). Small dots represent values for individual participants. Error bars indicate standard errors. Note that substantial evidence for the absence of a difference between change and no-change conditions was found for the peakGFR1 in Experiment 1 and 2, and for peakLFR1 in Experiment 1
Time to contact (a, b) and preloading phase duration (c, d) for Experiment 1 (a, c) and Experiment 2 (b, d). Symbols indicate the modality conditions (vision, haptic and visuohaptic) with light red and dark blue symbols for no-change (NC) and change (C) conditions, respectively. Groups of data are plotted for lifted light and heavy objects. Error bars represent standard errors and dots indicate individual participants
a Haptic cues (left) and objects (right). Size cues were used in Experiment 1 (large, medium and small; top pink objects) and material cues in Experiment 2 (wood, metal and stone; bottom). b Experimental setup. (1) Upper screen for showing force sensors. The screen is in a transparent state and shows the participant sitting behind the screen. (2) Lower screen for showing object in manipulandum (4). The screen had two side panels to hold it in place and participants moved their hand over the panel. (3) Start position of the right hand. A motion tracking sensor is taped on the hand. (4) The manipulandum, placed on a platform (blue box), with two force sensors, in which an object (pink cuboid) could be placed. The object was hidden under a paper cover (dark grey). (5) Opening in a cardboard box through which participants placed their left hand. (6) The left hand was placed on a cushion. The haptic cue (pink plate) was attached to the arm of a haptic device (7) and pressed on the hand palm. c Experimental time line, showing opening of the top screen and presentation of the cues. Illustrations below show the participant’s view of the screens in the vision and the visuohaptic condition. In the haptic condition, the lower screen remains opaque. First, the top screen opens to allow view of the sensors. Then, the 1st cue is presented accompanied by a beep. Next, the experimenter changes the objects and cues in case of a change condition. After the go-signal, the hand starts to move and when it reaches a threshold height, the 2nd cue is presented. The object is grasped, lifted and replaced
Sensory information about object properties, such as size or material, can be used to make an estimate of object weight and to generate an accurate motor plan to lift the object. When object properties change, the motor plan needs to be corrected based on the new information. The current study investigated whether such corrections could be made quickly, after the movement was initiated. Participants had to grasp and lift objects of different weights that could be indicated with different cues. During the reaching phase, the cue could change to indicate a different weight and participants had to quickly adjust their planned forces in order to lift the object skilfully. The object weight was cued with different object sizes (Experiment 1) or materials (Experiment 2) and the cue was presented in different sensory modality conditions: visually, haptically or both (visuohaptic). Results showed that participants could adjust their planned forces based on both size and material. Furthermore, corrections could be made in the visual, haptic and visuohaptic conditions, although the multisensory condition did not outperform the conditions with one sensory modality. These results suggest that motor plans can be quickly corrected based on sensory information about object properties from different sensory modalities. These findings provide insights into the information that can be shared between brain areas for the online control of hand-object interactions.
Group differences on DRRI-2 Sexual Harassment score for ST and NST groups
Brain pattern of signed t values of ST-NST comparison with absolute values corresponding to P < 0.000202, Bonferroni corrected for 247 multiple comparisons. See text for details
Frequency distribution of discriminant scores
Mahalanobis D² values for NST group
Mahalanobis D² values for the ST group
Previous research has documented the utility of synchronous neural interactions (SNI) in classifying women veterans with and without posttraumatic stress disorder (PTSD) and other trauma-related outcomes based on functional connectivity using magnetoencephalography (MEG). Here, we extend that line of research to evaluate trauma-specific PTSD neural signatures with MEG in women veterans. Participants completed diagnostic interviews and underwent a task-free MEG scan from which SNI was computed. Thirty-five women veterans were diagnosed with PTSD due to sexual trauma and sixteen with PTSD due to non-sexual trauma. Strength of SNI was compared in women with and without sexual trauma, and linear discriminant analysis was used to classify the brain patterns of women with PTSD due to sexual trauma and non-sexual trauma. Comparison of SNI strength between the two groups revealed widespread hypercorrelation in women with sexual trauma relative to those without sexual trauma. Furthermore, using SNI, the brains of participants were classified as sexual trauma or non-sexual trauma with 100% accuracy. These findings bolster evidence supporting the utility of task-free SNI and suggest that neural signatures of PTSD are trauma-specific.
Temporal lobe epilepsy (TLE) is the most common type of intractable epilepsy and is refractory to medications. However, the role and mechanism of H19 in regulating TLE remains largely undefined. Expression of H19 and miR-206 was detected using real-time quantitative PCR (RT-qPCR). Cell apoptosis, autophagy and inflammatory response were determined by flow cytometry, western blotting and enzyme-linked immunosorbent assay (ELISA). The interaction between H19 and miR-206 was predicted on the miRcode database and confirmed by luciferase reporter assay, RNA immunoprecipitation (RIP) and RNA pull-down. H19 was upregulated and miR-206 was downregulated in the rat hippocampus neurons after kainic acid (KA) treatment. Functionally, both H19 knockdown and miR-206 overexpression weakened KA-induced apoptosis, autophagy, inflammatory response, and oxidative stress in hippocampus neurons. Mechanically, the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway was activated by H19 knockdown and miR-206 was confirmed to be targeted and negatively regulated by H19. Moreover, downregulation of miR-206 could counteract the effects of H19 knockdown in KA-induced hippocampus neurons. Knockdown of H19 suppressed hippocampus neuronal apoptosis, autophagy and inflammatory response presumably through directly upregulating miR-206 and activating the PI3K/AKT signaling pathway.
Experimental set up for recording high-density surface electromyography and ultrasonography from vastus lateralis muscle. Electrode location of high-density surface electromyography and process of calculations of motor unit firing properties (bottom). Association between motor unit firing rate and recruitment threshold for back leg in a fencer and calculation of the slope (sMUFR) and intercept (mMUFR) for the detected motor units (right bottom). Probe position of ultrasonography and longitudinal ultrasound image for measuring muscle thickness of vastus lateralis muscle. The distance between superficial and deep aponeurosis of vastus lateralis was measured at the center of probe. MVC maximal voluntary contraction
Comparisons between front leg (FL) and back leg (BL) in maximal voluntary contraction (MVC) (A), muscle thickness (MT) (B), modified motor unit firing rate (mMUFR) (C), and unilateral vertical jump (UVJ) (D) for all participants on grouping both fencers with less (F3−) and more (F3+) than 3 years of fencing experience
Comparisons between front leg (FL) and back leg (BL) in maximal voluntary contraction (MVC) (A), muscle thickness (MT) (B), modified motor unit firing rate (mMUFR) (C), and unilateral vertical jump (UVJ) (B) for fencers with less (F3−) and more (F3+) than 3 years of fencing experience. *p < 0.05 between FL and BL
Representative data for relationships between motor unit recruitment threshold and firing rate for the fencer with less (F3−) (left) and more (F3+) (right) than 3 years of fencing experience for front (FL) (open circle) and back leg (BL) (filled circle)
Associations between front leg (FL) and back leg (BL) in maximal voluntary contraction (MVC) (A), muscle thickness (MT) (B), modified motor unit firing rate (mMUFR) (C), and unilateral vertical jump (UVJ) (D) for all participants, and fencers with less (F3−) (open circle) and more (F3+) (filled circle) than 3 years of fencing experience
In elite fencers, muscle strength and muscle mass of the front leg (FL) are greater than those of the back leg (BL) due to characteristic physiological and biomechanical demands placed on each leg during fencing. However, the development of laterality in their neural and muscular components is not well-understood. The present study investigated neuromuscular characteristics of FL and BL in junior fencers. Nineteen junior fencers performed neuromuscular performance tests for FL and BL, separately. There were no significant differences in the isometric knee extension strength (MVC), unilateral vertical jump (UVJ), vastus lateralis muscle thickness (MT), or motor unit firing rate of the vastus lateralis muscle (MUFR) between FL and BL (p > 0.05). In subgroup analyses, a significantly greater MUFR in FL than BL was noted only in fencers with > 3 years of fencing experience, and significantly greater UVJ in FL than BL was observed solely in fencers with < 3 years of fencing experience (p < 0.05). Strong positive correlations between FL and BL were identified in MVC, MT, and MUFR in fencers with > 3 years of fencing experience, but not in those with < 3 years of experience. These findings suggest that in junior fencers, laterality in neuromuscular performance has not manifested, whereas longer fencing experience induces fencing-dependent laterality in neural components, and laterality in dynamic muscle strength is decreased with fencing experience.
Sensory feedback from the foot sole plays an important role in shaping human locomotion. While net muscle activity and kinematic changes have been correlated with electrical stimulation to five topographical regions of the foot, it remains unknown if these responses are similar with tactile stimulation. The purpose of this study was to use texture in foot orthosis design, applied to five distinct regions under the foot sole, and measure joint kinematics, location of center of pressure, and muscle activity of eight lower leg muscles during level and incline walking. Fifty-five healthy adults completed 48 walking trials in textured and non-textured foot orthoses. Study results confirm that tactile stimulation is stimulation-site and gait-phase specific in modulating lower leg muscle activity during walking. For example, texture under the lateral forefoot consistently generated a suppression of EMG and texture under the lateral midfoot always generated a facilitation. In early stance, adding texture under the medial midfoot or calcaneus facilitated extensor muscle activity and suppressed flexor muscle activity. Texture under the lateral midfoot or medial forefoot facilitated tibialis posterior activation. These results support the topographical organization of cutaneous mechanoreceptors in foot sole skin while considering how texture can be used in foot orthosis design to target lower leg muscular changes during locomotion.
Patient selection flowchart. USN = unilateral spatial neglect
Modified Posner task screen used in the present experiment. A Valid trial, B Invalid trial
Modified Posner task performance. A Reaction time and B accuracy are depicted separately for the three study groups, the location where the target appeared, preceding cue (valid or invalid)
Unilateral spatial neglect (USN) is a common neurological syndrome that develops after a right hemisphere lesion. By examining the performance of the modified Posner task added to the vertical dimensions of the left and right visual fields, we studied whether the lower left area had different neglect symptoms than the other locations. 41 patients with right hemisphere damage were classified into those with mild USN (USN+ ; n = 20) and without USN (USN− ; n = 21). Twenty older participants made up the healthy control (HC; n = 20) group. All participants recorded deficits in the paper-and-pencil tests established for neglect and reaction times in the modified Posner task. In the paper-and-pencil tests, there was no difference in deficit between the upper and lower left visual fields in any of the groups. According to the modified Posner task, the USN+ group exhibited delays in reaction time in the lower left visual field rather than the upper left visual field. Importantly, reaction times were delayed, and USN symptoms persisted, particularly for the lower left quadrant. Our findings imply that the modified Posner task can accurately uncover neglect symptoms in the case of mild USN.
a Sample force pulse from one subject with Parkinson’s disease and definitions of dependent measures and phases of excitation, transition, and relaxation specified based on the 90% peak force level (F90). Representative isometric force pulses from an older adult (b) and a person with Parkinson’s disease (c). b and c Show overlaid pulses with markers at peak force to demonstrate the relative invariance in time to peak force in the healthy state (b) and prolonged, highly variable, time to peak force in some people with PD (c)
Relationships between the number of segments to F90 and time to F90 (a), RFD (b), duration of first segment (c) and RFD scaling factor (d). 7 older adults (OA) were able to reach 90% of the intended force with one segment of motor output. 7 OA and 4 people with Parkinson’s disease (PD) required 2 segments, 1 OA and 6 PD required 3 or more segments. Spearman’s correlations (ρ) indicate that segmentation had a marked association with time to F90, RFD and the scaling of RFD with peak force. Three or more segments marked a departure of PD from aging in this small sample of subjects. The duration of the first segment was not significantly different between groups and exhibited less of an association with segmentation. Note in panel d that the progression from one to two segments corresponds with a noticeable reduction in the RFD-SF, regardless of group
a RFD–peak force relationship in a single subject with Parkinson’s disease. This subject had a RFnD-SF of 7.0 and a median of 2 segments which, together, is more characteristic of the older adult group. However, the R² of .17 for this subject indicates the obvious inconsistency in force pulse performance that is caused by many pulses with two or more segments. The ideal RFD-SF line is drawn for the filled circles which represent single-segment pulses. The distribution of data points for the subset of single-segment pulses is similar to that observed in young adults who have R² values greater than 0.9 (Bellumori et al. 2011). The fact that pulses with single segments are possible in this individual (26/84 pulses with one segment, median pulse duration = 0.787 s) illustrates the inconsistent nature of disordered control and the fact that good control is still possible. b Relationship between Peak RFD and RFD-SF. Note the strong covariance between the ability to scale RFD with peak force and the ability to produce higher rates of force development
Some people with Parkinson’s disease (PD) have disruptions in motor output during rapid isometric muscle contractions. Measures of such disruptions (motor segmentation) may help clarify disease subtype, progression, or effects of therapeutic interventions. We investigated the potential utility of segmentation measures by testing two hypotheses that are fundamental to measurement and evaluation. First, measures of motor segmentation are reliable from day to day (intraclass correlation coefficient > 0.8). Second, that measures of motor segmentation have the sensitivity to differentiate between people with PD and older adults. 10 subjects with PD had a mean age of 70.1 years, Hoehn–Yahr stage < 3, and median levodopa equivalent daily dose of 350 mg. Older adult (mean age 81.9 years) reference data are from a previously published study. Each subject provided approximately 87 rapid isometric index finger abduction force pulses up to 65% of their maximal isometric force for calculation of force pulse measures. Measures were computed for the excitation, transition, and relaxation phases of each force pulse. Measures of motor segmentation had high reliability and presented large (Cohen’s D > 0.8) and significant (p < 0.05) group differences. In bivariate plots of selected measures, motor segmentation marked a departure of PD from age-related slowing. Across all subjects, greater segmentation was associated with greater impairments in rate control and a longer time to reach peak force (all Spearman’s ρ > 0.8). These results support the potential utility of the motor segmentation measures by satisfying requirements for reliability and the sensitivity to indicate deviations from age-related slowing in motor output.
A Paradigm structure—Four, five or six consecutive pictures of either healthy skin (neutral context) or of infectious skin (inhibitory context) were followed by a sexual target or a neutral control target. Both were masked with a scrambled version. Each context–target combination was shown ten times per session and participants watched three sessions. B Timing of one paradigm block. During the context priming skin pictures were shown for 2 s each. In eight blocks of each session, one of the skin pictures was replaced with a book (attention check). The target was displayed for 150 ms and followed by a mask (350 ms). The jittered pause lasted on average 2500 ms
Functional MRI results A Brain regions with increased activity in sexual versus control pictures (contrast for the whole sample, including all conditions), B increase activation in PD+HS relative to PD-HS when seeing sexual targets in comparison to control cues, C the bars represent increased activation during inhibitory context (H-) relative to non-inhibitory context (H+) for the peak voxels of the two significant clusters in the left medial frontal gyrus (left panel) and left superior frontal gyrus (right panel). H + neutral context, H- Inhibitory context, HS+ Hypersexual patients, HS- non-hypersexual patients, OFF/ON is referring to medication status, PD Parkinson’s disease. Color bars represent t-value
Hypersexuality in medicated patients with PD is caused by an increased influence of motivational drive areas and a decreased influence of inhibitory control areas due to dopaminergic medication. In this pilot study, we test a newly developed paradigm investigating the influence of dopaminergic medication on brain activation elicited by sexual pictures with and without inhibitory contextual framing. Twenty PD patients with and without hypersexuality were examined with fMRI either OFF or ON standardized dopaminergic medication. The paradigm consisted of a priming phase where either a neutral context or an inhibitory context was presented. This priming phase was either followed by a sexual or a neutral target. Sexual, compared to neutral pictures resulted in a BOLD activation of various brain regions implicated in sexual processing. Hypersexual PD patients showed increased activity compared to PD controls in these regions. There was no relevant effect of medication between the two groups. The inhibitory context elicited less activation in inhibition-related areas in hypersexual PD, but had no influence on the perception of sexual cues. The paradigm partially worked: reactivity of motivational brain areas to sexual cues was increased in hypersexual PD and inhibitory contextual framing lead to decreased activation of inhibitory control areas in PD. We could not find a medication effect and the length of the inhibitory stimulus was not optimal to suppress reactivity to sexual cues. Our data provide new insights into the mechanisms of hypersexuality and warrant a replication with a greater cohort and an optimized stimulus length in the future.
Individuals with cerebral palsy (CP) display motor control patterns that suggest decreased supraspinal input, but it remains unknown if they are able to modulate lower-limb reflexes in response to more complex tasks, or whether global motor control patterns relate to reflex modulation capacity in this population. Eight ambulatory individuals with CP (12–18 years old) were recruited to complete a task complexity protocol, where soleus H-reflex excitability was compared between bilateral (baseline) and unilateral (complex) standing. We also investigated the relationship between each participant’s ability to modulate soleus H-reflex excitability and the complexity of their walking neural control pattern determined from muscle synergy analysis. Finally, six of the eight participants completed an exoskeleton walking protocol, where soleus H-reflexes were collected during the stance phase of walking with and without stance-phase plantar flexor resistance. Participants displayed a significant reduction in soleus H-reflex excitability (− 26 ± 25%, p = 0.04) with unilateral standing, and a strong positive relationship was observed between more refined neural control during walking and an increased ability to modulate reflex excitability (R = 0.79, p = 0.04). There was no difference in neuromuscular outcome measures with and without the ankle exoskeleton (p values all > 0.05), with variable reflex responses to walking with ankle exoskeleton resistance. These findings provide evidence that ambulatory individuals with CP retain some capacity to modulate lower-limb reflexes in response to increased task complexity, and that less refined neural control during walking appears to be related to deficits in reflex modulation.
Purpose Speech production is a complex motor task involving multiple subsystems. The relationships between these subsystems need to be comprehensively investigated to understand the underlying mechanisms of speech production. The goal of this paper is to examine the differential contributions of 1) auditory and somatosensory feedback control mechanisms, and 2) laryngeal and articulatory speech production subsystems on speech motor control at an individual speaker level using altered auditory and somatosensory feedback paradigms. Methods Twenty young adults completed speaking tasks in which sudden and unpredictable auditory and physical perturbations were applied to the laryngeal and articulatory speech production subsystems. Auditory perturbations were applied to laryngeal or articulatory acoustic features of speech. Physical perturbations were applied to the larynx and the jaw. Pearson-product moment correlation coefficients were calculated between 1) auditory and somatosensory reflexive responses to investigate relationships between auditory and somatosensory feedback control mechanisms, and 2) laryngeal and articulatory reflexive responses as well as acuity measures to investigate the relationship between auditory-motor features of laryngeal and articulatory subsystems. Results No statistically significant correlations were found concerning the relationships between auditory and somatosensory feedback. No statistically significant correlations were found between auditory-motor features in the laryngeal and articulatory control subsystems. Conclusion Results suggest that the laryngeal and articulatory speech production subsystems operate with differential auditory and somatosensory feedback control mechanisms. The outcomes suggest that current models of speech motor control should consider decoupling laryngeal and articulatory domains to better model speech motor control processes.
Schematic of the timeline of visual and movement events for the short (top panel), medium (middle panel), and long movement preparation intervals. For each condition a fixation cross was presented and following a stable gaze a movement preparation interval of short (1000–2000 ms), medium (3000–4000 ms) and long (5000–6000 ms) duration was initiated (see grey rectangles). Following the preparation interval, the fixation cross was extinguished and a target was presented 200 ms thereafter (i.e., gap paradigm). The onset of the target (small light grey square) served as the cue to pro- or antisaccade and target presentation was 50 ms in duration
Panel A depicts reaction time (RT: ms) percent frequency distribution histograms for pro- and antisaccade task-switch and task-repeat trials in the short, medium and long movement preparation intervals. The light and dark grey rectangles denote anticipatory (i.e., < 100 ms) and short-latency (i.e., 100–150 ms) saccades, respectively. The histograms include trials involving inhibition failures and trials with RTs that exceeded 2.5 SDs of a participant- or task-specific mean. Only trials involving a directional error (i.e., a prosaccade instead of an instructed antisaccade or vice versa) or signal loss are excluded from the histograms. The presented mean depict RTs calculated before subsequent data post-processing. Panel B depicts post-processed participant-specific median RTs for pro- and antisaccade task-switch and task-repeat trials. Connecting lines emphasize the RT difference between task-switch and task-repeat trials for each participant. Black lines and error bars represent task-specific group means and associated 95% within-participant confidence intervals. Last, the inset panels depict group difference scores (i.e., task-switch minus task-repeat) for each task-type with error bars representing 95% between-participant confidence intervals. The absence of overlap between an error bar and zero indicates a reliable difference between task-switch and task-repeat trials
Panels A and B present group mean saccade duration (ms) and gain variability, respectively, for pro- and antisaccade task-switch and task-repeat trials. Error bars represent 95% between-participant confidence intervals
Cognitive flexibility is a core component of executive function and supports the ability to ‘switch’ between different tasks. Our group has examined the cost associated with switching between a prosaccade (i.e., a standard task requiring a saccade to veridical target location) and an antisaccade (i.e., a non-standard task requiring a saccade mirror-symmetrical to veridical target) in predictable (i.e., AABB) and unpredictable (e.g., AABAB…) switching paradigms. Results have shown that reaction times (RTs) for a prosaccade preceded by an antisaccade (i.e., task-switch trial) are longer than when preceded by its same task-type (i.e., task-repeat trial), whereas RTs for antisaccade task-switch and task-repeat trials do not differ. The asymmetrical switch-cost has been attributed to an antisaccade task-set inertia that proactively delays a subsequent prosaccade (i.e., the unidirectional prosaccade switch-cost). A salient question arising from previous work is whether the antisaccade task-set inertia passively dissipates or persistently influences prosaccade RTs. Accordingly, participants completed separate AABB (i.e., A = prosaccade, B = antisaccade) task-switching conditions wherein the preparation interval for each trial was ‘short’ (1000–2000 ms; i.e., the timeframe used in previous work), ‘medium’ (3000–4000 ms) and ‘long’ (5000–6000 ms). Results demonstrated a reliable prosaccade switch-cost for each condition (ps < 0.02) and two one-sided test statistics indicated that switch cost magnitudes were within an equivalence boundary (ps < 0.05). Hence, null and equivalence tests demonstrate that an antisaccade task-set inertia does not passively dissipate and represents a temporally persistent feature of oculomotor control.
Experimental set up for the hand task (left) and the foot task (right). Yellow circles represent the tappers used to deliver the vibrotactile targets to the dorsum of the right hand or right foot, while green circles represent the LEDs used to present the visual distractors at near and far locations. The white dots represent the fixation points used for near and far distractors. The distance of the visual distractors from the touched limb (near vs. far distractors) was manipulated in different blocks of trials. Within each block, the relative location of the tactile target and of the visual distractor was selected randomly (higher vs. lower locations are labelled as ‘top’ and ‘bottom’ and indicated by the letter T and B in the figure). The tactile target and the simultaneous visual distractors were presented at the same relative location on congruent trials (both top or both bottom locations), while they were presented at different relative locations on incongruent trials (one top and the other bottom and vice-versa)
Schematic representation of the timeline of the trial events
The CCE measured in the hand task (left) and foot task (right), shown separately for near visual distractors (light grey) and far visual distractors (dark grey). Error bars represent the standard error of the means. The asterisks indicate the significance level of the pairwise contrasts: **p < .01; *p < .05
Peripersonal space (PPS), the space closely surrounding the body, is typically characterised by enhanced multisensory integration. Neurophysiological and behavioural studies have consistently shown stronger visuo-tactile integration when a visual stimulus is presented close to the tactually stimulate body part in near space (within PPS) than in far space. However, in the majority of these studies, tactile stimuli were delivered to the upper limbs, torso and face. Therefore, it is not known whether the space surrounding the lower limbs is characterised by similar multisensory properties. To address this question, we asked participants to complete two versions of the classic visuo-tactile crossmodal congruency task in which they had to perform speeded elevation judgements of tactile stimuli presented to the dorsum of the hand and foot while a simultaneous visual distractor was presented at spatially congruent or incongruent locations either in near or far space. In line with existing evidence, when the tactile target was presented to the hand, the size of the crossmodal congruency effect (CCE) decreased in far as compared to near space, suggesting stronger visuo-tactile multisensory integration within PPS. In contrast, when the tactile target was presented to the foot, the CCE decreased for visual distractors in near than far space. These findings show systematic differences between the representation of PPS around upper and lower limbs, suggesting that the multisensory properties of the different body part-centred representations of PPS are likely to depend on the potential actions performed by the different body parts.
A Experimental setting for the self-motion perception testing. The subject seats on rotatory chair and maneuvers the pointer (P) to pursuit the remembered visual target (T) presented before the rotation. The head is pitched 30° nose down and the rotation is performed in the horizontal plane (arrow). B Target tracking during symmetric and asymmetric rotation. The tracking during symmetric sinusoidal rotation (upper two traces) and during asymmetric sinusoidal rotation (lower two traces) (T, tracking; S, stimulus) are reported. The black spots represent the initial and the final position of the target representation. Below: tracking calibration. Note that the final position of the target representation is correct after symmetric rotation, since no spatial disparity is present between the initial and final position. Conversely, the target representation is erroneous after asymmetric rotation as shown by the disparity of the initial and final position (FPE, final position error). The inclined lines, fitting the tracking during slow rotation, show the progressive reduction of slow-motion perception during asymmetric rotation
Head position in three conditioning head position: upright (A), supine (B) and prone (C). The head is quickly rotated toward one side (solid arrow) and slowly rotated back to the center (dashed arrow). In all positions the direction of fast rotation is toward the right horizontal semicircular canals (RSC) and induces an intense right canal activation. Conversely, the fast dynamic influence of the gravity vector on the otolithic receptors is different during asymmetric rotation: the otolithic receptors are not influenced by gravity in (A) and they are activated in the other two cases, but the direction of the dynamic modulation of otolith and canal is opposite in supine (B) compared with prone (C) position
Activation of the horizontal semicircular canal and otolithic receptors during yaw rotation in supine (nose up, left side) and prone (nose down, right side) head position. In nose up and nose down the direction of the fast rotation (solid arrow) is the same for the horizontal semicircular canal, whereas the direction of fast activation by gravity is opposite for the otolithic receptors. U: Utricle, S: Sacculus. In nose up the rotation of the gravity vector displaced the otoliths toward the external side of the head (the arrow shift to the Ext), while in node down the gravity rotation displaces the otoliths toward the internal side (the arrow shift to Int). Vertical dashed line represents the head midline
Magnitude of the FPE after conditioning with different numbers of head asymmetric yaw rotation in upright position. The FPE was induced by 4 cycles of whole-body asymmetric yaw rotation in upright position. Box, whisker, horizontal line and square represent range, quartile, median and mean, respectively. In abscissa the cycles of conditioning. FPE without prior conditioning (0) and after different yaw head asymmetric conditioning: 4 cycles, (4); 8 cycles (8), 16 cycles (16). Note that only the FPE after 16 cycles conditioning is significantly increased compared with that without conditioning (***p < 0.001)
Conditioning effect of yaw asymmetric head rotation at different head positions on FPE induced by 4-cycle whole-body asymmetric yaw rotation. Box, whisker, horizontal line and square represent range, quartile, median and mean, respectively. In abscissa the conditioning position. The FPE observed without conditioning (non-conditioning) and the FPE after conditioning in supine (supine), upright (upright) and prone (prone) position. Note FPE significantly increases after conditioning in supine compared to the FPE after conditioning in upright position (***p < 0.001) and to the FPE without conditioning (***p < 0.001). Moreover, the FPE after prone conditioning is significantly lower than that observed without conditioning (**p < 0.01)
This study aimed to test the role of the otolithic system in self-motion perception by examining adaptive responses to asymmetric off-axis vertical rotation. Self-movement perception was examined after a conditioning procedure consisting of prolonged asymmetric sinusoidal yaw rotation of the head on a stationary body with hemicycle faster than the other hemicycle. This asymmetric velocity rotation results in a cumulative error in spatial self-motion perception in the upright position that persists over time. Head yaw rotation conditioning was performed in different head positions: in the upright position to activate semicircular canals and in the supine and prone positions to activate both semicircular canals and otoliths with the phase of otolithic stimulation reversed with respect to activation of the semicircular canals. The asymmetric conditioning influenced the cumulative error induced by four asymmetric cycles of whole-body vertical axis yaw rotation. The magnitude of this error depended on the orientation of the head during the conditioning. The error increased by 50% after upright position conditioning, by 100% in the supine position, and decreased by 30% in the prone position. The enhancement and reduction of the perceptual error are attributed to otolithic modulation because of gravity influence of the otoliths during the conditioning procedure in supine and prone positions. These findings indicate that asymmetric velocity otolithic activation induces adaptive perceptual errors such as those induced by semicircular canals alone, and this adaptation may be useful in testing dynamic otolithic perceptual responses under different conditions of vestibular dysfunction.
In the clinical treatment of Parkinson’s disease (PD), the emergence of l-DOPA-induced dyskinesia (LID) and other motor symptoms remains a restrictive factor for the use of levodopa (l-DOPA). Our objective was to test the effect of continuous dopaminergic stimulation (CDS) on LID and the mechanism of its effect on the calcium (Ca²⁺) signaling pathway. 6-OHDA (6-hydroxydopamine)-treated rats were administered 1% CMC-Na, l-DOPA, rotigotine behenate (RGTB), and l-DOPA + RGTB, respectively, for 28 days. During the treatment, the abnormal involuntary movement (AIM) scores were conducted on days 1, 5, 10, 14, 19, 23 and 28 after the first dose. Subsequently, the number of tyrosine hydroxylase (TH)-positive neurons was detected by immunohistochemistry. Additionally, the changes in Ca²⁺ were detected using a laser confocal technique, and the related proteins, such as neuronal NOS (nNOS), BAX, BCl2, CaMKII, P-CaMKII, and PSD-95, were measured by Western blot. Transmission electron microscopy (TEM) was used to investigate the changes in synaptic structure. The data showed that CDS reduced the AIM scores, increased the expression of TH in the substantia nigra (SN), decreased the expression of nNOS and BAX/BCL2ratio in the striatum, reduced the Ca²⁺ influx induced by l-DOPA and inhibited the Ca²⁺ signaling pathways of dopamine neurons in the striatum. Moreover, the overactivity of synapses induced by L-DOPA was inhibited by CDS. These data further support the hypothesis that continuous delivery of a dopamine agonist reduces the risk of LID induction. Moreover, RGTB could be a promising treatment for PD by simulating CDS.
An example from the Minefield Task (MFT. A The chessboard in the acquisition phase; participants were allowed to see the mine locations. B The chessboard without the mines on it; participants were allowed to see it after being unblindfolded. Green and Red circles indicated the start and the end of the route to plan
The Corsi Block Tapping test (on the table) (CBT, Corsi 1972) and the Walking Corsi Test (Piccardi et al. 2008a, 2013). Note that the WalCT consists of a larger version of the CBT (3 m × 2.5 m; scale 1:10)
Regression plots for the Minefield Task (MFT) versus Corsi Block Tapping Test (CBT), Walking Corsi Test (WalCT) and Tower of London (ToL-16)
Travel planning (TP) is a kind of planning devoted to spatial orientation that is distinguishable from general planning (GP). It is crucial to reach a destination, since it allows to select the best route according to the environmental features (e.g., the one with little traffic or the safest). TP is also needed to avoid obstacles along the way and to put in place effective strategies to support navigation. TP involves several cognitive processes, such as visuo-spatial and topographic memory as well as other executive functions (i.e., general planning, cognitive flexibility, problem solving, and divergent thinking) and it is affected by internal factors (such as gender, cognitive strategies, age). Here, we focused on the effects of visuo-spatial (VSWM) and topographic (TWM) working memory on TP, using the Minefield Task (MFT), a new tool aimed at testing TP. We tested VSWM, TWM, GP, and TP in 44 college students. First, we checked for gender differences in all the tasks proposed and then assessed the relation among VSWM, TWM, GP, and TP. Results showed that even though gender difference could be found on TWM, GP, and TP, significative correlations emerged among TP, VSWM, and GP as well as a tendency to significance for VSWM and GP in the regression analyses. Though more evidence is needed, these results suggest that when a brand-new route is computed, GP and VSWM can be the most relevant processes, whereas topographic memory was less involved, probably because the MFT does not require to recall a route from memory. The implications of these results in clinical settings are discussed.
Stimuli for the hand laterality task: photographs of left and right human hands shown from both back and palm views were presented at eight different angles of rotation between 0 and 315 degrees. The example shows right-hand stimuli presented from the back view
Mean RT (upper panel) and accuracy (lower panel) for each angle of rotation by group (YA younger adults, OA older adults, PD participants with Parkinson’s disease) and hand view (palm; back). Error bars represent SEM
Mean RT (upper panel) and accuracy (lower panel) for lateral and medial orientations by group and view
Mean RT (left panel) and accuracy (right panel) for each angle of rotation in the letter rotation task in each group (YA younger adults, OA older adults, PD participants with Parkinson’s disease). Error bars represent SEM
Motor imagery supports motor learning and performance and has the potential to be a useful strategy for neurorehabilitation. However, motor imagery ability may be impacted by ageing and neurodegeneration, which could limit its therapeutic effectiveness. Motor imagery can be assessed implicitly using a hand laterality task (HLT), whereby laterality judgements are slower for stimuli corresponding to physically more difficult postures, as indicated by a “biomechanical constraint” effect. Performance is also found to differ between back and palm views of the hand, which may differentially recruit visual and sensorimotor processes. Older adults and individuals with Parkinson’s disease (PD) have shown altered performance on the HLT; however, the effects of both ageing and PD on laterality judgements for the different hand views (back and palm) have not been directly examined. The present study compared healthy younger, healthy older, and PD groups on the HLT, an object-based mental rotation task, and an explicit motor imagery measure. The older and PD groups were slower than the younger group on the HLT, particularly when judging laterality from the back view, and exhibited increased biomechanical constraint effects for the palm. While response times were generally similar between older and PD groups, the PD group showed reduced accuracy for the back view. Letter rotation was slower and less accurate only in the PD group, while explicit motor imagery ratings did not differ significantly between groups. These results suggest that motor imagery may be slowed but relatively preserved in both typical ageing and neurodegeneration, while a PD-specific impairment in visuospatial processing may influence task performance. The findings have implications for the use of motor imagery in rehabilitation protocols.
Maternal exposure to anti-epileptic drug Valproic acid (VPA) during pregnancy increases the risk for the development of autism spectrum disorders (ASD). In this study, we have examined whether prenatal exposure to VPA will alter expression of key genes, synaptic morphology of nerve growth factor (NGF) and Reelin expressing neurons in the cortex of male offspring. To characterize in animal models, rat fetuses were exposed to VPA on 12.5 gestational day. The offspring of the VPA-exposed individuals (42%) resembles ASD-related phenotype (facial malformation, crooked-like tail, flattened paw, toenails and in-turning-ankles). Furthermore, we have observed deficit in social interaction accompanied by deregulation in expression of genes such as Caspase-3, focal adhesion kinase (FAK), Reelin, glial fibrillary acidic protein (GFAP), proliferating cell nuclear antigen (PCNA) and NGF. Subsequently, immunohistochemistry analysis revealed that exposure to VPA alters the cytoarchitecture (area, diameter) and reduced the dendritic arborization of Reelin, NGF expressing neurons in cortex. The compromised neurodevelopment by altered expression of Caspase-3, FAK, Reelin, GFAP, PCNA and NGF may cause defects in neuronal architecture, synaptic formation, synaptic plasticity and neuronal communication which could be linked with observed ASD-like phenotype and deficit social interaction.
A Illustration of the cable-driven robotic system and the application of bilateral pelvis perturbation. B Illustration of the flow diagram of a randomized-controlled crossover study protocol. C Illustration of the varied pelvis perturbation during the course of the 10 min adaptation period. Perturbation force was demonstrated as the percentage of maximal tolerated force [%]
The average error size of the margin of stability (MoS) during the adaptation and post-adaptation periods in the anodal and sham conditions. A step-by-step average of the changes in MoS during the first 200 steps of the adaptation period. B step-by-step average of the changes in MoS during the first 15 steps after the removal of the perturbation force during the post-adaptation period. Each curve represents the average of the changes in MoS across participants. The shaded areas represent the standard error of the changes in MoS for each testing condition. To better visualize the difference between conditions, the group-mean curve was smoothed with a span of 5% of the total number of data points. C Lines indicate the average change values ± standard error across participants in the two conditions. Asterisks indicate statistically significant difference, p < 0.05. D The box plots of the step numbers counted before the MoS re-entered CIlate during the early adaptation period for the anodal and sham conditions. Bars indicate the average values ± standard error across participants
Mean integrated muscle activities across participants during baseline, the early adaptation, the late adaptation, the early post-adaptation, and the late post-adaptation periods in the anodal and sham conditions. EMG data were normalized to baseline values of each condition. Asterisks indicate a statistically significant difference between the anodal and sham conditions, p < .05. Adapt adaptation
Deficits in locomotor function, including impairments in walking speed and balance, are major problems for many individuals with incomplete spinal cord injury (iSCI). However, it remains unclear which type of training paradigms are more effective in improving balance, particularly dynamic balance, in individuals with iSCI. The purpose of this study was to determine whether anodal transcutaneous spinal direct current stimulation (tsDCS) can facilitate learning of balance control during walking in individuals with iSCI. Fifteen individuals with iSCI participated in this study and were tested in two sessions (i.e., tsDCS and sham conditions). Each session consisted of 1 min of treadmill walking without stimulation or perturbation (baseline), 10 min of walking with either anodal tsDCS or sham stimulation, paired with bilateral pelvis perturbation (adaptation), and finally 2 min of walking without stimulation and perturbation (post-adaptation). The outcome measures were the dynamic balance, assessed using the minimal margin of stability (MoS), and electromyography of leg muscles. Participants demonstrated a smaller MoS during the late adaptation period for the anodal tsDCS condition compared to sham (p = 0.041), and this MoS intended to retain during the early post-adaptation period (p = 0.05). In addition, muscle activity of hip abductors was greater for the anodal tsDCS condition compared to sham during the late adaptation period and post-adaptation period (p < 0.05). Results from this study suggest that anodal tsDCS may modulate motor adaptation to pelvis perturbation and facilitate learning of dynamic balance control in individuals with iSCI.
Participant ready position (left), target presentation (middle), movement end (right)
Peak acceleration of the light and heavy stylus in controls and subclinical neck pain. Asterisks indicates significant difference
Spatial variability of kinematic markers peak acceleration, peak velocity, peak deceleration, and endpoint in the dominant (right hand) and non-dominant (left hand) arm. Asterisks indicates significant difference
Subclinical neck pain (SCNP) refers to recurrent neck pain and/or stiffness for which individuals have not yet sought treatment. Prior studies have shown that individuals with SCNP have altered cerebellar processing that exhibits an altered body schema. The cerebellum also plays a vital role in upper limb reaching movements through refining internal models and integrating sensorimotor information. However, the impact of SCNP on these processes has yet to be examined in the context of a rapid goal-directed aiming response that relies on feedforward and feedback processes to guide the limb to the target. To address this, SCNP and control participants performed goal-directed upper limb movements with the dominant and non-dominant hands using light and heavy styli in the horizontal plane. The results show greater peak accelerations in SCNP participants using the heavy stylus. However, there were no other group differences seen, possibly due to the fact that reaching behavior predominantly relies on vision such that any proprioceptive deficits seen in those with SCNP can be compensated. This study illustrates the robust compensatory nature of the CNS when performing end-effector reaching tasks, suggesting studies altering visual feedback may be needed to see the full impact of SCNP on upper limb aiming.
Experimental schedule, immobilization procedure, and visual simple reaction time task. A On Day 1, the measurements of the pre-restraint state were performed from 18:00. In the transcranial magnetic stimulation (TMS) group, the corticospinal excitability [motor-evoked potential (MEP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF)] and motor performance were evaluated. In the somatosensory-evoked potential (SEP) group, the SEPs and motor performance were evaluated. On Day 2, the right upper extremity was restrained for 10 h from 8:00 to 18:00, and measurements were performed immediately after the restraint ended. B Immobilization procedure: the subjects were covered with a bandage from the fingertips to the wrist. The wrist and forearm were in an intermediate position, and the sling was used to limit the motion of the right upper limb in a 90° elbow flexion limb position. C Visual simple reaction time task: after a 500-ms presentation of a fixation point (+ shape) at the center of the CRT display, a target stimulus (○ shape) was presented for 50 ms at the same location. The interstimulus interval (ISI) was 1–2 s. The participants were instructed to press the button as soon as possible after the target stimulus was presented. One hundred trials were conducted with each hand
Ground average waveform of the somatosensory-evoked potential (SEP) derived from each median nerve stimulation on both hands at pre- and post-immobilization. Ground average waveform of SEPs during the median nerve stimulation of A the restrained hand and B the unrestrained hand. The gray and black lines indicate the SEPs at pre-immobilization and post-immobilization. The black arrows indicate the respective SEP components. *p < 0.05
Changes in motor performance pre- and post-immobilization: resting motor threshold (rMT), motor-evoked potential (MEP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). A The rMT (n = 10) and B MEP of the first dorsal interosseous muscle of both the restrained hand (right hand) and unrestrained hand (left hand) are shown as mean values (± SEM) before (Pre) and after (Post) restraint. The white and black bars indicate the data for the unrestrained and restrained hands, respectively. C The SICI and D ICF of both the restrained hand and unrestrained hand are shown before (Pre) and after (Post) restraint. The white and black circles indicate the data for the unrestrained hand and restrained hand, respectively. The black bars indicate the median. *p < 0.05 and **p < 0.01
Changes in motor performance pre- and post-immobilization: pinch force and visual simple reaction time. A The pinch force (n = 19) of both the restrained hand (right hand) and unrestrained hand (left hand) are shown as mean values (± SEM) pre- and post-immobilization. The white and black bars indicate the data for the unrestrained and restrained hands, respectively. B The visual simple reaction time (n = 18) of both the restrained hand and unrestrained hand (left hand) are shown pre- and post-immobilization. The white and black circles indicate the data for the unrestrained and restrained hands, respectively. The black bars indicate the median. *p < 0.05 and **p < 0.01
Functional changes in sensory-motor cortex and motor-related areas due to upper limb immobilization. Left panel (normal state): As a comparator system, the PMC monitors the error between the sensory prediction based on the motor program and the actual sensory feedback (Garbarini et al. 2019). Right panel (post-immobilization): PMC activity increases when sensory input is restricted for a certain period of time by short-term upper limb immobilization. In this case, the information of sensory prediction from the SMA is not input to the PMC because there are no movements. It is possible that the PMC monitors not only the error between the somatosensory prediction and the somatosensory feedback but also the state of the somatosensory input at steady state. In addition, although the anatomical and pathophysiological mechanisms are unclear, reduced muscle contraction and sensory input may increase PMC/SMA excitability. The decrease in corticospinal tract excitability caused by short-term upper limb immobilization may not be due to changes in excitability within M1, but may be influenced by regions other than M1 (PMC, SMA, or M1). Black, gray, and white circles indicate inactive, normal, and active, respectively
Several studies have reported the effects of short-term immobilization of the upper limb on the excitability of the primary motor cortex. In a report examining the effects of upper limb immobilization on somatosensory information processing using somatosensory-evoked potentials (SEPs), short-term upper limb immobilization reduced the amplitude and increased the latency of the P45 component recorded over the contralateral sensorimotor cortex of SEPs. However, the effects of upper limb immobilization on other regions involved in somatosensory information processing are unknown. Therefore, we investigated the effects of short-term right upper limb immobilization on sensory information processing, particularly in motor-related areas, by measuring the cortical components of SEPs. We also evaluated the excitability of the primary motor cortex and corticospinal tract as well as motor performance (visual simple reaction time and pinch force) related to these areas. All subjects were divided into two groups: the SEP group, in which the effects of upper limb immobilization on the excitability of somatosensory processing were investigated, and the transcranial magnetic stimulation (TMS) group, in which the effects of upper limb immobilization on the excitability of the corticospinal tract and primary motor cortex were investigated. Motor performance was evaluated in all subjects. We showed that 10-h right upper limb immobilization increased the cortical component of SEPs (N30) in the SEP group and decreased the excitability of the corticospinal tract, but not of the primary motor cortex, in the TMS group. The pinch force decreased after upper limb immobilization. However, the visual simple reaction time did not change between pre- and post-immobilization. The supplementary motor area and premotor cortex are believed to be the source of the N30. Therefore, these results suggest that upper limb immobilization affected somatosensory information processing in motor-related areas. Moreover, 10-h right upper limb immobilization reduced the excitability of corticospinal tracts but not that of the primary motor cortex, suggesting that circuits outside the M1, such as the intra- and inter-hemispheric inhibitory and facilitatory circuits rather than circuits within the M1, may be responsible for the reduced excitability of the central nervous system after restraint.
Concentrations of metabolites of several neurotransmitters in the striatum of VGF-overexpressing mice. Concentrations of glutamic acid (A), GABA (B), 5-HIAA (C), DOPAC (D), and HVA (E) in the striatum. Concentrations of glutamic acid (F), GABA (G), 5-HIAA (H), DOPAC (I), and HVA (J) in the cerebral cortex. Data are expressed as mean ± SEM. (n = 4 or 5). *p < 0.05 vs. wild-type mice (Student’s t test). DOPAC 3 4-Dihydroxyphenylacetic acid; 5-HIAA 5-Hydroxyindoleactic acid; HVA homovanillic acid; GABA gamma-aminobutyric acid; Tg VGF-overexpressing mice; WT wild-type mice; SEM standard error of mean
The relative concentrations of several metabolites in the striatum and cerebral cortex. Concentrations of N-acetyl-l-asprtic acid (A) and meso-erythritol (B) in the striatum. Data are expressed as mean ± SEM. (n = 4 or 5). * p < 0.05 vs. wild-type mice (Student’s t-test). The other metabolites are listed in Supplemental Table 1. Tg VGF-overexpressing mice; WT wild-type mice; SEM standard error of mean
The upregulation of VGF-derived peptide after administration of MK-801. A Total distance was scored for each 10 min period. Thirty min after starting open field test, MK-801 (0.1 or 0.3 mg/kg) was administrated. Data are expressed as mean ± SEM. (n = 8). ##p < 0.01 vs. vehicle-treated group (Dunnett’s test). B The ratio between activity before administration and after administration. Data are expressed as mean ± SEM. (n = 8). ##p < 0.01 vs. vehicle-treated group (Dunnett’s test). C The expression level of VGF-derived peptide (NAPP129 named VGF20) relative to β-actin. Data are expressed as the mean fold difference versus vehicle-treated group ± SEM (n = 8). #p < 0.05 vs. vehicle-treated group (Dunnett’s test). Representative bands from the western blot analysis of NAPP129 and β-actin are shown at the top. Veh vehicle; SEM standard error of mean
Locomotor enhancing effects of MK-801 in VGF-overexpressing mice. A Total distance was scored for each 10 min period. Thirty min after starting open field test, MK-801 (0.1 mg/kg) was administrated. Data are expressed as mean ± SEM. (n = 4 to 8). **p < 0.01 vs. vehicle-treated wild-type (two-tailed Student’s t-test). B The ratio between activity before administration and after administration. Data are expressed as mean ± SEM. (n = 5–10). *p < 0.05, **p < 0.01 MK-801-treated VGF-overexpressing mice (Tukey’s test). Tg VGF-overexpressing mice; WT wild-type mice; SEM standard error of mean
Schematic image of VGF-derived peptides involved in glutaminergic dysfunction in mice. VGF-overexpressing mice were more sensitive to MK-801
VGF nerve growth factor inducible (VGF) is a neuropeptide precursor, which is induced by several neurotrophic factors, including nerve growth factor and brain-derived neurotrophic factor. Clinically, an upregulation of VGF levels has been reported in the cerebrospinal fluid and prefrontal cortex of patients with schizophrenia. In our previous study, mice overexpressing VGF exhibited schizophrenia-related behaviors. In the current study, we characterized the biochemical changes in the brains of VGF-overexpressing mice. Metabolomics analysis of neurotransmitters revealed that glutamic acid and N-acetyl-l-aspartic acid were increased in the striatum of VGF-overexpressing mice. Additionally, the present study revealed that MK-801, which causes the disturbance in glutamic acid metabolism, increased the expression level of VGF-derived peptide (NAPP129, named VGF20), and VGF-overexpressing mice had higher sensitivity to MK-801. These results suggest that VGF may modulate the regulation of glutamic acid levels and the degree of glutamic acid signaling.
Blood oxygen level dependent (BOLD) signal in functional magnetic resonance imaging (fMRI) is frequently used as a proxy for underlying neural activity. Although this is a plausible assumption for experiments where a task is performed, it may not hold to the same degree for conditions of fMRI recording in a task-free, “resting” state where neural synaptic events are weak and, hence, neurovascular coupling and endothelial vascular factors become more prominent (Hillman Annu Rev Neurosci 37:161–181, 2014, 10.1146/annurev-neuro-071013-014111). Here we investigated the magnitude of change of BOLD in consecutive samples over the acquisition time period (turnover of BOLD, “TBOLD”) by first-order differencing of single-voxel BOLD time series acquired in 70 areas of the cerebral cortex of 57 cognitively healthy women in a task-free resting state. More specifically, we evaluated (a) the variation of TBOLD among different cortical areas, (b) its dependence on age, and (c) its dependence on the presence (or absence) of the neuroprotective Human Leukocyte Antigen (HLA) gene DRB1*13 (DRB1*13:02 and DRB1*13:01). We found that TBOLD (a) varied substantially by 2.2 × among cortical areas, being highest in parahippocampal and entorhinal areas and lowest in parietal-occipital areas, (b) was significantly reduced in DRB1*13 carriers across cortical areas (from ~ 15% reduction in orbitofrontal cortex to 2% reduction in cuneus), and (c) increased with age in noncarriers of DRB1*13 but decreased with age in DRB1*13 carriers. These findings document significant dependencies of TBOLD on cortical area location, HLA DRB1*13 and age.
Schematic representation of the attentional gate model (AGM).
Adapted from Zakay and Block (1996, 1997)
Example of the trials used in the time perception task. The “ + ” sign was repeated with 1-s interval rhythm 10 times. The intervals between key pressings of the participants were considered as time reproduction. Responses were recorded until the participant declared that 3 min is over (time production).
Adapted from Nazari et al. (2020)
Median and mean data for time reproduction and production (T-corrected) of control (gray color) and experimental (white color) groups. As can be seen at the right panel, the produced time in time production task was significantly increased after SMR–Beta1 NFB training in the experimental group in comparison to controls. However, no such effect was observed in the time reproduction task (left panel). **significance (α < 0.01) Horizontal lines in the boxes represents the median of data. Plus sign indicates mean of the data
Left panel: the influence of NFB training on SMR-Beta1 indicating pre and post-test mean amplitudes in both experimental and control groups. As can be seen, the mean of SMR-Beta1 was significantly increased in the experimental group. Error bars represent the SEM of data. **significance (α < 0.01). Right panel: the NFB training perforamance and T-corrected measures of the time production task. The scatterplot indicates that increased SMR-Beta1 was positivly correlated with T-corrected scores
The timing ability plays an important role in everyday activities and is influenced by several factors such as the attention and arousal levels of the individuals. The effects of these factors on time perception have been interpreted through psychological models of time, including Attentional Gate Model (AGM). On the other hand, research has indicated that neurofeedback (NFB) training improves attention and increases arousal levels in the clinical and healthy population. Regarding the link between attentional processing and arousal levels and NFB and their relation to time perception, this study is a pilot demonstration of the influence of SMR–Beta1 (12–18 Hz) NFB training on time production and reproduction performance in healthy adults. To this end, 12 (9 female and 3 males; M = 26.3, SD = 3.8) and 12 participants (7 female and 5 males; M = 26.9, SD = 3.1) were randomly assigned into the experimental (with SMR–Beta1 NFB) and control groups (without any NFB training), respectively. The experimental group underwent intensive 10 sessions (3 days a week) of the 12–18 Hz up-training. Time production and reproduction performance were assessed pre and post NFB training for all participants. Three-way mixed ANOVA was carried out on T-corrected scores of reproduction and production tasks. Correlation analysis was also performed between SMR–Beta1 and time perception. While NFB training significantly influenced time production (P < 0.01), no such effect was observed for the time reproduction task. The results of the study are finally discussed within the frameworks of AGM, dual-process and cognitive aspects of time perception. Overall, our results contribute to disentangling the underlying mechanisms of temporal performance in healthy individuals.
Mean RTs (A) and accuracy rates (B) on corresponding (Cs) and noncorresponding (Nc) trial types for ET patients and HC. Error bars reflect standard error of the mean
Conditional accuracy functions for corresponding (A, Cs) and non-corresponding (B, Nc) trial types for ET patients and HC
RT delta plots for ET patients and HC. Each bin contains the same number of trials, averaged across the subjects in each subgroup
Essential tremor (ET) is a movement disorder characterized primarily by action tremor which affects the regulation of movements. Disruptions in cerebello-thalamocortical networks could interfere with cognitive control over actions in ET, for example, the ability to suppress a strong automatic impulse over a more appropriate action (conflict control). The current study investigated whether ET impacts conflict control proficiency. Forty-one ET patients and 29 age-matched healthy controls (HCs) performed a conflict control task (Simon task). Participants were instructed to give a left or right response to a spatially lateralized arrow (direction of the arrow). When the action signaled by the spatial location and direction of the arrow were non-corresponding (induced conflict), the inappropriate action impulse required suppression. Overall, ET patients responded slower and less accurately compared to HCs. ET patients were especially less accurate on non-corresponding conflict (Nc) versus corresponding (Cs) trials. A focused analysis on fast impulsive response rates (based on the accuracy rate at the fastest reaction times on Nc trials) showed that ET patients made more fast errors compared to HCs. Results suggest impaired conflict control in ET compared to HCs. The increased impulsive errors seen in the ET population may be a symptom of deficiencies in the cerebello-thalamocortical networks, or, be caused by indirect effects on the cortico-striatal pathways. Future studies into the functional networks impacted by ET (cortico-striatal and cerebello-thalamocortical pathways) could advance our understanding of inhibitory control in general and the cognitive deficits in ET.
Boxplot (with median, first and third quartiles, and range) showing that SAI was superior in the Higher- compared to the Lower-Memory group
Scatterplot showing that SAI was significantly associated with the Episodic Memory composite
Episodic memory is vulnerable to aging and may be influenced by age-related decline in the neurotransmitter acetylcholine. We probed this relation using a novel, minimally invasive transcranial magnetic stimulation marker of brain acetylcholine: short-latency afferent inhibition (SAI). We used neuropsychological testing to construct a composite score of episodic memory in N = 19 community-dwelling older adults, and stratified older adults into Higher- (N = 9) versus Lower-memory (N = 10) groups before SAI. The Higher-memory group showed significantly stronger SAI than the Lower-memory group, indicating an association between higher brain acetylcholine levels and better episodic memory. The two memory groups were equivalent in the potential confounds of age, education, mood, subjective sleep quality, and executive function. These data converge with others to suggest that episodic memory is related to acetylcholine in older adults. This relation should be further investigated, especially with pharmacology and neuroimaging.
Illustration of the experimental procedure. Note. In the familiarization phase, Pac-man was presented in the center flanked by two rectangles during the fixation period. Once infants fixated on the Pac-man in the center, the Pac-man crawled either to the right or to the left. Under the color condition, the Pac-man crawled toward the color-defined rectangle while ignoring its orientation. Under the orientation condition, the Pac-man crawled toward the orientation-defined rectangle while ignoring its color. Feature binding between orientation and color is not required in the current task (Treisman and Gelade, 1980). The familiarization phase consisted of eight trials followed by the anticipation-looking phase of eight trials
The results of Experiment 1. Note. Mean proportion of anticipation-looking in each condition. Error bars represent SE. **p < 0.01 against the chance level 0.5
The result of Experiment 2. Note. Mean proportion of anticipation-looking in color condition. Error bar represents SE. **p < 0.01 against the chance level 0.5
When looking for an object, we identify it by selectively focusing our attention to a specific feature, known as feature-based attention. This basic attentional system has been reported in young children; however, little is known of whether infants could use feature-based attention. We have introduced a newly developed anticipation-looking task, where infants learned to direct their attention endogenously to a specific feature based on the learned feature (color or orientation), in 60 preverbal infants aged 7–8 months. We found that preverbal infants aged 7–8 months can direct their attention endogenously to the specific target feature among irrelevant features, thus showing the feature-based attentional selection. Experiment 2 bolstered this finding by demonstrating that infants directed their attention depending on the familiarized feature that belongs to a never-experienced object. These results that infants can form anticipation by color and orientation reflect they could drive their attention through feature-based selection.
Experimental setup, stimulation–torque response, and data analysis. A Schematic of the experimental setup and EMG feedback. B Torque–time profiles from a participant across 3 stimulation intensities for femoral nerve (solid lines) and quadriceps stimulation (dashed lines). Stimulation was applied at time 0. The torque recordings were completed with the knee at 90° degrees. C Example traces representing the average-rectified SOL EMG from 35 trials from a single participant illustrating the heteronymous effects from femoral nerve and quadriceps stimulation onto ongoing SOL EMG. The solid black horizontal line represents the mean SOL EMG during a 400 ms period prior to stimulation (feedback target was 20% MVIC). The solid grey horizontal lines represent 1 SD above and below the mean background SOL EMG. Excitatory onset was determined as the SOL EMG trace exceeding the mean + 1 SD for ≥ 2 ms and excitatory end when returning below the mean + 1 SD line for ≥ 2 ms. Only excitatory traces with onset ≥ 23 ms after stimulation were considered as arising from Ia feedback (Hultborn et al. 1987; Meunier et al. 1990) (e.g., muscle stimulation caused stimulation artifacts in some cases as shown in the example). The area (the inhibition area shown on the figure in grey was calculated using trapz in matlab and referenced to the mean background EMG) and duration of excitation were calculated using the onset and end timepoints. The same analyses were completed for inhibition using mean – 1SD
Femoral nerve and quadriceps stimulation evoked torque responses across intensities. The box plot indicates the distribution of torque magnitudes for each intensity. Each participant is shown as a number
Heteronymous excitation from femoral nerve and quadriceps stimulation onto SOL across the three stimulation intensities. The box plot indicates the sample data distribution for each intensity, and the numbers represent each participant
Heteronymous inhibition onset, magnitude, and duration from femoral nerve and quadriceps stimulation onto SOL across the three stimulation intensities. A Inhibition onset was determined as the time when SOL EMG went 1 SD below the mean background SOL EMG. The magnitude of heteronymous inhibition expressed as B EMG area (%MVIC∙ms) and C as the mean background subtracted SOL EMG during a window from 35 to 73 ms after stimulation. D The duration of heteronymous inhibition was determined as period that EMG went 1 SD below the mean background SOL EMG for ≥ 2 ms and returned above the 1 SD mean background EMG line for ≥ 2 ms. The box plots indicate the sample data distribution for each intensity and condition, and the numbers represent each participant
Hypothesized heteronymous spinal circuit pathways involved during femoral nerve and quadriceps stimulation onto ongoing soleus EMG. A During femoral nerve stimulation, activation of Ia axons (green lines) provide the most parsimonious explanation for heteronymous excitation. Activation of Ib axons (blue lines) and motor axons (purple line) acting via the Renshaw cell as recurrent inhibition are the most likely inputs responsible for heteronymous inhibition. The motor evoked twitch contraction is presumed to have additionally provided inhibitory feedback by mechanically activating the Golgi tendon organs. B Quadriceps stimulation with surface electrodes resulted in decreased frequency and magnitude of excitatory responses suggesting reduced activation of Ia axons (green dotted line) compared to femoral nerve stimulation and thus presumably also reduced direct activation of Ib axons. The most parsimonious explanation for heteronymous inhibition was Ib afferent firing (blue lines) due to the twitch contraction and recurrent inhibition due to motor axon antidromic inputs acting via Renshaw cells (purple line). Q quadriceps, SOL soleus, GTO Golgi tendon organ, MN motoneuron
Heteronymous excitatory feedback from muscle spindles and inhibitory feedback from Golgi tendon organs and recurrent inhibitory circuits can influence motor coordination. The functional role of inhibitory feedback is difficult to determine, because nerve stimulation, the primary method used in humans, cannot evoke inhibition without first activating the largest diameter muscle spindle axons. Here, we tested the hypothesis that quadriceps muscle stimulation could be used to examine heteronymous inhibition more selectively when compared to femoral nerve stimulation by comparing the effects of nerve and muscle stimulation onto ongoing soleus EMG held at 20% of maximal effort. Motor threshold and two higher femoral nerve and quadriceps stimulus intensities matched by twitch evoked torque magnitudes were examined. We found that significantly fewer participants exhibited excitation during quadriceps muscle stimulation when compared to nerve stimulation (14–29% vs. 64–71% of participants across stimulation intensities) and the magnitude of heteronymous excitation from muscle stimulation, when present, was much reduced compared to nerve stimulation. Muscle and nerve stimulation resulted in heteronymous inhibition that significantly increased with increasing stimulation evoked torque magnitudes. This study provides novel evidence that muscle stimulation may be used to more selectively examine inhibitory heteronymous feedback between muscles in the human lower limb when compared to nerve stimulation.
Alzheimer’s disease (AD) is a neurodegenerative disease that seriously affects the life and health of the elderly. Studies have found that circular RNAs (circRNAs) are associated with human diseases, including AD. Hsa_circ_0049472 has been uncovered to be overexpressed in AD, but the role of circ_0049472 remains unclear. AD patients were recruited to collect cerebrospinal fluid (CSF) and serum samples. Amyloid beta (Aβ)-induced SK-N-SH and CHP-212 cells were used as the AD cell models in vitro. Quantitative real-time PCR (qRT-PCR) was used to assess the expression of circ_0049472, microRNA-107 (miR-107) and kinesin family member 1B (KIF1B). Cell counting kit-8 assay tested the cell viability, and flow cytometry measured cell apoptosis. The levels of proliferating cell nuclear antigen (PCNA), BCL2 Associated X (Bax) and kinesin family member 1B (KIF1B) protein were examined by western blot. In addition, the relative inflammatory cytokines (TNF-α, IL-6 and IL-1β) were detected by enzyme-linked immunosorbent assay (ELISA). The malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were measured by relative kits. Dual-luciferase reporter assays and RNA pull-down assay verified the relationship between miR-107 and circ_0049472 or KIF1B. Circ_0049472 and KIF1B were overexpressed in AD patient-derived cerebrospinal fluid (CSF) and serum samples, as well as Aβ-induced SK-N-SH and CHP-212 cells. Silencing circ_0049472 promoted cell proliferation, and inhibited cell apoptosis in Aβ-induced SK-N-SH and CHP-212 cells. MiR-107 was a target of circ_0049472. MiR-107 silencing abolished the cell viability and apoptosis affected by down-regulation of circ_0049472 in Aβ-induced SK-N-SH and CHP-212 cells. Besides, miR-107 targeted KIF1B, and overexpressed KIF1B reverted miR-107 elevation-mediated effects on cell apoptosis, inflammation, and oxidative stress of Aβ-induced SK-N-SH and CHP-212 cells. Circ_0049472 modulated KIF1B by serving as a miR-107 decoy, thereby mediating Aβ-induced neurotoxicity, suggesting that circ_0049472 may be involved in AD pathogenesis.
It is unknown how hypohydration influences fine motor performance training and motor learning. Here, 30 participants (aged 19–46 years) were randomly assigned to a hypohydration (HYPO) or control (CON) group (both n = 15). Moderate hypohydration (~ 2.4% loss in body mass) was produced in HYPO via active dehydration before a 46 min fluid restricted rest period was undertaken. The conclusion of rest coincided with when CON attended the facilities. Both groups undertook a discrete sequence production task consisting of 6 training blocks, and returned ~ 300 min later to complete a delayed retention and transfer test while euhydrated. Bilateral pre-frontal cortex (PFC) haemodynamics were assessed using functional near-infrared spectroscopy throughout training and delayed learning assessments. Response time improved across training ( P < 0.01) and was similar between the groups (both P = 0.22). Analysis of training PFC haemodynamics revealed a significant group by block interaction for oxygenated (O 2 Hb; P < 0.01), but not deoxygenated haemoglobin ( P = 0.77). In training block 1, bilateral O 2 Hb was higher in HYPO ( P = 0.02), while bilateral O 2 Hb increased in CON between blocks 2–3 and 5–6 (both P ≤ 0.03). During the delayed retention and transfer test, no group differences or interactions were found in response time, response error, or PFC haemodynamics (all P ≥ 0.27). Moderate hypohydration does increase PFC activation during motor skill learning, however, this appears to be transient and of little consequence to training or delayed retention or transfer performance.
The evidence for the hemispheric specialization of motor planning reveals several inconsistencies between the left-lateralized hypothesis and a distributed system across the hemispheres. We compared participants with left hemiplegic cerebral palsy (HCP) to right-handed control subjects in this study's first experiment by inviting them to perform a motor planning task. Participants were required to release the start button, grasp a hexagon, and rotate it according to the instructions. In the second experiment, we compared left-HCP subjects with right-HCP subjects inviting them to perform the same task (we used the data for left-HCP subjects from the first experiment). P2 amplitude, as well as planning time, grasping time, releasing time, and initial grip selection planning patterns, were used as outcome measures in both experiments. The first experiment revealed that controls acted more quickly and chose more effective planning patterns. Also, the P2 amplitude was smaller in left-HCP subjects than in control subjects. No significant group effect was observed in the second experiment for any movement-related measure or P2. At the neural level, however, there was an interaction between 'region' and 'group,' indicating the distinction between the two groups in the right region. The results are discussed in terms of motor planning's hemispheric distribution and individual differences in the HCP group.
Block diagram of the online control using EMG feedback with two encoding schemes, spatial (SC) and combined spatio-frequency (SFC) modulation. The left side of the figure shows the subject, wearing an ic splint and the Myo Armband on the dominant forearm and the stimulation system with the electrode array wrapped circumferentially around the dominant upper arm. The stimulator was placed on a table connected to the computer via Bluetooth. The EMG recorded by the Myo Armband was rectified, low-pass filtered (0.5 Hz) and normalized to a percentage of MVC (50%). The myoelectric signal was sent to the computer, as well as back to the user through electrotactile feedback. The right side of the figure depicts the subject’s view during the experimental session, where a computer monitor displayed the tasks to be performed in the experiment (e.g., the target muscle activation interval and the trial number)
The electrotactile EMG feedback delivered to the subject for the two feedback resolutions (higher and lower) and codes (SC and SFC). The normalized myoelectric signal was divided into 5 and 3 intervals (white and grey stripes) in the higher (left panels) and lower (right panels) resolution, respectively. In SC (upper panels, in blue), the momentary interval in which the generated myoelectric signal (black line) resided was indicated by activating different electrodes with a fixed frequency of 60 Hz. In SFC (lower panels, shades of red), the spatial activation was supplemented with frequency modulation (4–60 Hz) conveying the magnitude of the myoelectric signal within the “active” interval. Note that in the SFC panels, the line still indicates the myoelectric signal, but the color represents the frequency of stimulation associated with the signal value (within the interval), as specified by the color map
Representative myoelectric signals generated by one subject using higher resolution (upper panel) and lower resolution (lower panel) feedback and two coding schemes (SC—left plots and SFC—right plots). The task for the subject was to use the feedback to reach and maintain the indicated target interval (blue shading). The generated signals are shown using light lines (for a total of 20 trials), while the solid black lines indicate the mean values and the shaded green area is ± 1 standard deviation. The SFC coding seems to improve the performance (decreased variability and overshooting/undershooting) but only for the lower resolution feedback
performance across the two electrotactile codes (SFC and SC) for higher (upper panel) and lower resolution (lower panel). From left to the right, the boxplots show the medians and 25 and 75 percentiles of rising time, overshooting rate, undershooting rate, variability and absolute deviation for each electrotactile code. Asterisks indicate statistically significant differences. *p < 0.05; **p < 0.01; ***p < 0.001
Electrotactile stimulation has been commonly used in human–machine interfaces to provide feedback to the user, thereby closing the control loop and improving performance. The encoding approach, which defines the mapping of the feedback information into stimulation profiles, is a critical component of an electrotactile interface. Ideally, the encoding will provide a high-fidelity representation of the feedback variable while being easy to perceive and interpret by the subject. In the present study, we performed a closed-loop experiment wherein discrete and continuous coding schemes are combined to exploit the benefits of both techniques. Subjects performed a muscle activation-matching task relying solely on electrotactile feedback representing the generated myoelectric signal (EMG). In particular, we investigated the performance of two different coding schemes (spatial and spatial combined with frequency) at two feedback resolutions (low: 3 and high: 5 intervals). In both schemes, the stimulation electrodes were placed circumferentially around the upper arm. The magnitude of the normalized EMG was divided into intervals, and each electrode was associated with one interval. When the generated EMG entered one of the intervals, the associated electrode started stimulating. In the combined encoding, the additional frequency modulation of the active electrode also indicated the momentary magnitude of the signal within the interval. The results showed that combined coding decreased the undershooting rate, variability and absolute deviation when the resolution was low but not when the resolution was high, where it actually worsened the performance. This demonstrates that combined coding can improve the effectiveness of EMG feedback, but that this effect is limited by the intrinsic variability of myoelectric control. Our findings, therefore, provide important insights as well as elucidate limitations of the information encoding methods when using electrotactile stimulation to convey a feedback signal characterized by high variability (EMG biofeedback).
Task conditions: unimanual (unimanual right shown here), bimanual independent-goal and bimanual common-goal condition
Effect of task conditions (unimanual-UNI; bimanual common goal-CG; bimanual independent goal-IG) on A) Reach-to-Grasp time (RTG time) and B) Peak grasp aperture (PGA) in control (CON), RHD, and LHD groups. Solid circles represent the dominant arm for controls/non-paretic arm for LHD and RHD groups. Open circles represent the non-dominant arm for controls/paretic arm for LHD and RHD groups. Significance levels represented are: * = p < 0.05. Error bars represent ± standard error of the mean (SEM)
Differences in bimanual coordination between control (CON), RHD and LHD of (A) reach coordination, (B) grasp coordination and (C) pick-up coordination during the three task conditions. Positive time lags indicate that the paretic arm (or non-dominant arm for neurotypical controls) lags. Negative time lags indicate that the non-paretic arm (the dominant arm for neurotypical controls) lags. Significance levels represented are: * = p < 0.05. Error bars represent ± standard error of the mean (SEM)
Clinical predictors of bimanual grasp coordination deficits in patients with left-hemisphere damage and right-hemisphere damage by task goal. A Upper extremity Fugl–Meyer scores significantly related to bimanual grasp coordination deficits to common and independent goals for individuals with LHD. B In individuals with RHD, upper extremity Fugl–Meyer scores was not significantly related to bimanual grasp coordination. C For the LHD group, Trail-Making Test scores did not significantly relate to bimanual grasp coordination deficits. D In contrast, Trail-Making Test scores significantly related to grasp coordination deficits to common and independent goals for the RHD group
The perceptual feature of a task such as how a task goal is perceived influences performance and coordination of bimanual actions in neurotypical adults. To assess how bimanual task goal modifies paretic and non-paretic arm performance and bimanual coordination in individuals with stroke affecting left and right hemispheres, 30 participants with hemispheric stroke (15 right-hemisphere damage—RHD); 15 left-hemisphere damage—LHD) and 10 age-matched controls performed reach-to-grasp and pick-up actions under bimanual common-goal (i.e., two physically coupled dowels), bimanual independent-goal (two physically uncoupled dowels), and unimanual conditions. Reach-to-grasp time and peak grasp aperture indexed motor performance, while time lags between peak reach velocities, peak grasp apertures, and peak pick-up velocities of the two hands characterized reach, grasp, and pick-up coordination, respectively. Compared to unimanual actions, bimanual actions significantly slowed non-paretic arm speed to match paretic arm speed, thus affording no benefit to paretic arm performance. Detriments in non-paretic arm performance during bimanual actions was more pronounced in the RHD group. Under common-goal conditions, movements were faster with smaller peak grasp apertures compared to independent-goal conditions for all groups. Compared to controls, individuals with stroke demonstrated poor grasp and pick-up coordination. Of the patient groups, patients with LHD showed more pronounced deficits in grasp coordination between hands. Finally, grasp coordination deficits related to paretic arm motor deficits (upper extremity Fugl–Meyer score) for LHD group, and to Trail-Making Test performance for RHD group. Findings suggest that task goal and distinct clinical deficits influence bimanual performance and coordination in patients with left- and right-hemispheric stroke.
Cerebellar ataxia is a neurodegenerative disorder leading to severe motor incoordination. Recently, it has been suggested that cannabinoids play a role in modulating ataxic symptoms. To understand the possible therapeutic effect of cannabinoids for the management of cerebellar ataxia, we used cannabinoid agonist/antagonists to target the cannabinoid type 1 receptor (CB1R) in the 3 acetyl pyridine (3AP) rat model of ataxia. The role of the CB1R was examined using three different doses of the CB1R agonist, WIN-55,212–2 (WIN; 0.1, 0.5, 1 mg/kg) administrated 30 min prior to 3AP (55 mg/kg, i.p.) which leads to motor impairment through destruction of the inferior olive. In some groups, the CB1R antagonist AM251 (1 mg/kg) was given in combination with WIN. Locomotor activity and motor coordination were impaired by 3AP, and the application of WIN did not ameliorate this effect. However, the abnormal gait, rearing and grooming caused by 3AP were prevented by co-administration of AM251 with WIN. While the addition of the CB1R antagonist improved some ataxic symptoms, there was no effect of AM251 on balance or locomotor activity when co-administrated with WIN. Behavioral testing indicated that not only did WIN fail to exert any protective effect on ataxic symptoms; it exacerbated ataxic symptoms, suggesting that CB1R agonists may not be the ideal therapeutic drug in this disorder. When taken together, the findings from the present study indicate that cannabinoid modulation of ataxia symptoms may not act solely through CB1Rs and other cannabinoid receptors should be considered in future studies.
Overhead view of the experimental setup during both arm cycling (A) and tonic contraction (C) trials for a right-hand dominant individual. Curved arrows indicate the direction of the intended movement. A chain was used to lock the arm cranks in place for the tonic contraction trial. EMG electrodes are located over the biceps brachii of both arms. Rectified EMG traces recorded from the non-dominant biceps brachii muscle are displayed from a representative subject during arm cycling (B) and an intensity-matched tonic contraction (D). The arrow represents the magnetic stimulation artifact. The regions between the sets of dashed vertical lines represent the regions of EMG that were compared. In both figures, the inset depicts the iSP (abscissas) following TMS. In the inset in B, the black trace represents stimulated EMG compared to the control EMG (gray trace) taken exactly 1 s later from the subsequent, non-stimulated EMG burst. In D, the inset depicts the iSP during tonic contraction. The gray rectangle portrays the post-inhibitory rebound of EMG that is present following the iSP during arm cycling (B) but not tonic contraction (D)
Group data for bEMG (A), iSP duration (B), and iSP EMG (C) during arm cycling (dark gray boxes) and tonic contraction (light gray boxes). Data are from those participants who displayed a clear iSP in both conditions (n = 8). Horizontal lines denote the minimum, first quartile, median, third quartile, and maximum values. * Denotes significant difference between conditions (p < 0.05)
Task-dependent changes in inhibition may explain why supraspinal excitability is higher during arm cycling than an intensity- and position-matched tonic contraction. The present study investigated whether interhemispheric inhibition (IHI) associated with biceps brachii activity was different during arm cycling, a locomotor output, compared to a tonic contraction. IHI was quantified using an ipsilateral silent period (iSP) evoked via transcranial magnetic stimulation (TMS) of the ipsilateral motor cortex. TMS was delivered at 120% resting motor threshold during the mid-elbow flexion phase of arm cycling (6 o’clock position, made relative to a clock face) and during a position- and intensity-matched tonic contraction. In total, 36 participants took part in the study. However, only 14 participants demonstrated IHI during arm cycling and 10 participants during tonic contraction. Of these participants, eight displayed clear iSPs during arm cycling and tonic contraction. The iSP duration was longer during arm cycling than tonic contraction (p < 0.05), while iSP EMG amplitude and area were not different between tasks (p > 05 for both comparisons). The main finding from this study is that IHI appears to be stronger during arm cycling than an intensity- and position-matched tonic contraction. This does not support previous findings of higher supraspinal excitability during arm cycling.
Right middle frontal gyrus showing greater activation differences (TFCE approach) between urn and draw choices in the ICD+ as compared to the ICD− group
a–c Cerebellar regions showing greater activation differences (uncorrected p < .0005) between urn choices under 80/20 and 60/40 probability in the ICD− as compared to the ICD+ group. d Right frontal pole showed greater activation differences (uncorrected p < .0005) between win and loss feedback in the ICD+ as compared to the ICD− group. For all panels, the right side of each image corresponds to the patients’ left side
Regions showing positive associations (at the TFCE level) between urn-specific activation and the number of draws. Note that smaller draw values reflect more impulsivity. The right side of the image corresponds to the patients’ left side. The key for the abbreviations can be found in the notes of Table 4
Regions showing negative associations (at the TFCE level) between win-specific activation and the number of draws. Scatter plots illustrate the association between impulsiveness and activation for selected areas; note that smaller draw values reflect more impulsivity. The right side of each image corresponds to the patients’ left side. The key for the abbreviations can be found in the notes of Table 4
Some patients with Parkinson’s disease (PD) experience impulse control disorders (ICDs), characterized by deficient voluntary control over impulses, drives, or temptations regarding excessive hedonic behavior. The present study aimed to better understand the neural basis of impulsive, risky decision making in PD patients with ICDs by disentangling potential dysfunctions in decision and outcome mechanisms. We collected fMRI data from 20 patients with ICDs and 28 without ICDs performing an information gathering task. Patients viewed sequences of bead colors drawn from hidden urns and were instructed to infer the majority bead color in each urn. With each new bead, they could choose to either seek more evidence by drawing another bead (draw choice) or make an urn-inference (urn choice followed by feedback). We manipulated risk via the probability of bead color splits (80/20 vs. 60/40) and potential loss following an incorrect inference ($10 vs. $0). Patients also completed the Barratt Impulsiveness Scale (BIS) to assess impulsivity. Patients with ICDs showed greater urn choice-specific activation in the right middle frontal gyrus, overlapping the dorsal premotor cortex. Across all patients, fewer draw choices (i.e., more impulsivity) were associated with greater activation during both decision making and outcome processing in a variety of frontal and parietal areas, cerebellum, and bilateral striatum. Our findings demonstrate that ICDs in PD are associated with differences in neural processing of risk-related information and outcomes, implicating both reward and sensorimotor dopaminergic pathways.
A A single intravenous (IV) administration of CN-105 (0.2 mg/kg) improved vestibulomotor function compared to vehicle treatment (**P < 0.01), as assessed by Rotarod when administered 30 min after TBI, and also at 10- and 20- minutes prior to injury (**P < 0.01). B When CN-105 0.05 mg/kg IV was administered 30 min prior to TBI, pretreatment was associated with improved functional performance (**P < 0.01) but at 60 min there was a reduction in protective effect (n = 11 in control group, n = 14 in all treatment groups)
Co-administration of CN-105 by intravenous (0.1 mg/kg) and intraperitoneal injection (0.5 mg/kg) for 3 or 6 h before the induction of TBI resulted in a durable improvement of vestibulomotor function for up to 28 days after injury as assessed by Rotarod. (***P < 0.001 for pretreatment 3 h vs. control; **P < 0.01 pretreatment 6 h prior to control)
Mean CN-105 plasma concentration as a function of time following an intravenous (IV) or intraperitoneal (IP) injection of 1 mg/kg CN-105 in sterile saline. The data represent the mean ± the standard error of 3 animals per time point per dose group
A A reduction in F4/80+ hippocampal microgliosis following treatment with CN-105 as compared to vehicle. At higher magnification, ramified microglial morphology is more evident in untreated mice. Formal unbiased stereology revealed a reduction in number of hippocampal F4/80 microglia as a function of treatment (*P < 0.05). B A trend toward reduced cortical microgliosis in animals treated with CN-105 compared to vehicle was observed, but did not achieve statistical significance
The treatment of traumatic brain injury (TBI) in military populations is hindered by underreporting and underdiagnosis. Clinical symptoms and outcomes may be mitigated with an effective pre-injury prophylaxis. This study evaluates whether CN-105, a 5-amino acid apolipoprotein E (ApoE) mimetic peptide previously shown to modify the post-traumatic neuroinflammatory response, would maintain its neuroprotective effects if administered prior to closed-head injury in a clinically relevant murine model. CN-105 was synthesized by Polypeptide Inc. (San Diego, CA) and administered to C57-BL/6 mice intravenously (IV) and/or by intraperitoneal (IP) injection at various time points prior to injury while vehicle treated animals received IV and/or IP normal saline. Animals were randomized following injury and behavioral observations were conducted by investigators blinded to treatment. Vestibulomotor function was assessed using an automated Rotarod (Ugo Basile, Comerio, Italy), and hippocampal microglial activation was assessed using F4/80 immunohistochemical staining in treated and untreated mice 7 days post-TBI. Separate, in vivo assessments of the pharmacokinetics was performed in healthy CD-1. IV CN-105 administered prior to head injury improved vestibulomotor function compared to vehicle control-treated animals. CN-105 co-administered by IP and IV dosing 6 h prior to injury also improved vestibulomotor function up to 28 days following injury. Microglia counted in CN-105 treated specimens were significantly fewer (P = 0.03) than in vehicle specimens. CN-105 improves functional outcomes and reduces hippocampal microglial activation when administered prior to injury and could be adapted as a pre-injury prophylaxis for soldiers at high risk for TBI.
This study investigated transfer of training from upper extremity limbs (the index fingers) to the lower extremity limbs (the legs) for performance of three gait sequences of different difficulty. Fifteen subjects participated in the study. Subjects in an iPad training group practiced by sequentially moving their left-and right-hand index fingers across tiles to each of three targets displayed on an iPad for 20 trials. Subjects in a gait training group practiced by sequentially walking across tiles to each of the 3 targets displayed on a screen for 20 trials. A no practice group did not receive practice trials. Immediately following practice of each level of difficulty, a transfer test (20 trials) was given for which subjects walked to the target just practiced. A retention test of 36 trials (12 trials at each difficulty level) was administered 20 min following performance of the last transfer test trial. The retention test showed that reaction times were shorter for the iPad training than gait training and no training groups; anticipatory postural adjustment times were equivalent for the iPad and gait training groups, but shorter than for the no training group; and movement times were shorter for the iPad training group than for the gait training and no training groups. These results suggest that iPad training (upper extremity) followed by performance of gait training (lower extremity) had greater benefits for learning (as measured by the delayed retention test) the gait sequences than practicing the actual gait sequences themselves.
a From top to bottom, representative single electromyographic (EMG) trace during eversion isometric contraction, full wave rectified EMG, smoothed EMG (average period: 5 ms), and averaged EMG (~ 30 sweeps), respectively. All signals were time-locked with respect to the electrical stimulation (0 ms; the vertical dotted line). The hatched area shows the time window for the middle latency reflex (MLR, ~ 70–120 ms after the electrical stimulation). b Full-wave rectified and averaged EMG signals in the peroneus longus (PL) muscle after the electrical stimulation during different degrees of eversion isometric contraction (5–40% of EMGmax). The vertical dotted lines indicate the time when electrical stimulation was applied. The hatched areas indicate the time window for calculating the MLR magnitude. The magnitude of MLR was measured as the difference between the baseline and peak values during the time window. A linear regression analysis between the magnitude of the MLR and BG EMG was performed to assess the reflex gain of the MLR. The slope of the calculated linear regression equation was used as MLR gain
Typical recordings of full-wave rectified and averaged electromyographic(EMG) signals in the peroneus longus (PL) muscle before(− 100 ms) and after (300 ms) electrical stimulation to the sural nerve in a control individual (neutral standing: upper left panel; inversion standing: upper right panel) and a chronic ankle instability patient (neutral standing: bottom left panel; inversion standing: bottom right panel) at different degrees of isometric eversion (~ 5–40% of the EMGmax). The vertical dotted lines represent the time when the electrical stimulation was delivered. The hatched areas show the duration of the inhibitory middle latency reflex (MLR) during which the inhibitory peak was measured
Grand means and standard deviations of the middle latency reflex (MLR) gains from individual data in each task for each group (gray bars: control; black bars: chronic ankle instability). The significance levels of multiple post hoc comparisons are indicated with asterisks (CAI vs. Control; ***p < 0.001), and dagger (Neutral vs. 30° inversion; †††p < 0.001)
The grand mean and standard deviation values of the reflex ratio (magnitude of MLR/background EMG) of the suppressive middle latency reflex (MLR) in 6 angle patterns of inversion standing (− 10°, 0°, 10°, 15°, 25°, and 30°) for all participants (open circle: control; closed circle: chronic ankle instability). The statistical significance for multiple post hoc comparisons is indicated with dagger (neutral 0° position vs. 15°, 25°, and 30° for patients with chronic ankle instability; ††p < 0.01, †††p < 0.001) and asterisks (CAI vs. Control; *p < 0.05, **p < 0.01, ***p < 0.001)
Grand mean and standard deviations of the passive and active angle position replication error from individual data for each participant (gray bars: control; black bars: chronic ankle instability). The significance levels on the t-test are indicated with asterisks (***p < 0.001)
This study aimed to investigate how the cutaneous reflexes in the peroneus longus (PL) muscle are affected by changing the ankle joint position in patients with chronic ankle instability (CAI). We also investigated the correlation between the degree of reflex modulation and angle position sense of the ankle joint. The participants were 19 patients with CAI and 20 age-matched controls. Cutaneous reflexes were elicited by applying non-noxious electrical stimulation to the sural nerve at the ankle joint in the neutral standing and eversion/inversion standing positions. The suppressive middle latency cutaneous reflex (MLR; ~ 70–120 ms) and angle position sense of the ankle joint were assessed. During neutral standing, the gain of the suppressive MLR was more prominent in the CAI patients than in controls, although no significant difference was seen during 30° inversion standing. In addition, the ratios of the suppressive MLR and background electromyography in a neutral position were significantly larger than those at the 15°, 25°, and 30° inversion positions in CAI patients. No such difference was seen in control individuals. Furthermore, the correlations between reflex modulation degree and position sense error were quite different in CAI patients compared to controls. These findings suggest that the sensory-motor system was deteriorated in CAI patients due to changes in the PL cutaneous reflex pathway excitability and position sense of the ankle joint.
Top-cited authors
Charles Spence
  • University of Oxford
Vladimir M Zatsiorsky
  • Pennsylvania State University
Lars Arendt-Nielsen
  • Aalborg University
Salvatore Maria Aglioti
  • Sapienza University of Rome
Michal Lavidor
  • Bar Ilan University